Assessment of Myocardial Microstructural Dynamics by In Vivo Diffusion Tensor Cardiac Magnetic Resonance.

BACKGROUND: Cardiomyocytes are organized in microstructures termed sheetlets that reorientate during left ventricular thickening. Diffusion tensor cardiac magnetic resonance (DT-CMR) may enable noninvasive interrogation of in vivo cardiac microstructural dynamics. Dilated cardiomyopathy (DCM) is a condition of abnormal myocardium with unknown sheetlet function. OBJECTIVES: This study sought to validate in vivo DT-CMR measures of cardiac microstructure against histology, characterize microstructural dynamics during left ventricular wall thickening, and apply the technique in hypertrophic cardiomyopathy (HCM) and DCM. METHODS: In vivo DT-CMR was acquired throughout the cardiac cycle in healthy swine, followed by in situ and ex vivo DT-CMR, then validated against histology. In vivo DT-CMR was performed in 19 control subjects, 19 DCM, and 13 HCM patients. RESULTS: In swine, a DT-CMR index of sheetlet reorientation (E2A) changed substantially (E2A mobility ∼46°). E2A changes correlated with wall thickness changes (in vivo r2 = 0.75; in situ r2 = 0.89), were consistently observed under all experimental conditions, and accorded closely with histological analyses in both relaxed and contracted states. The potential contribution of cyclical strain effects to in vivo E2A was ∼17%. In healthy human control subjects, E2A increased from diastole (18°) to systole (65°; p < 0.001; E2A mobility = 45°). HCM patients showed significantly greater E2A in diastole than control subjects did (48°; p < 0.001) with impaired E2A mobility (23°; p < 0.001). In DCM, E2A was similar to control subjects in diastole, but systolic values were markedly lower (40°; p < 0.001) with impaired E2A mobility (20°; p < 0.001). CONCLUSIONS: Myocardial microstructure dynamics can be characterized by in vivo DT-CMR. Sheetlet function was abnormal in DCM with altered systolic conformation and reduced mobility, contrasting with HCM, which showed reduced mobility with altered diastolic conformation. These novel insights significantly improve understanding of contractile dysfunction at a level of noninvasive interrogation not previously available in humans.

Comparison of 3 T and 1.5 T for T2* magnetic resonance of tissue iron.

BACKGROUND: T2* magnetic resonance of tissue iron concentration has improved the outcome of transfusion dependant anaemia patients. Clinical evaluation is performed at 1.5 T but scanners operating at 3 T are increasing in numbers. There is a paucity of data on the relative merits of iron quantification at 3 T vs 1.5 T. METHODS: A total of 104 transfusion dependent anaemia patients and 20 normal volunteers were prospectively recruited to undergo cardiac and liver T2* assessment at both 1.5 T and 3 T. Intra-observer, inter-observer and inter-study reproducibility analysis were performed on 20 randomly selected patients for cardiac and liver T2*. RESULTS: Association between heart and liver T2* at 1.5 T and 3 T was non-linear with good fit (R (2) = 0.954, p < 0.001 for heart white-blood (WB) imaging; R (2) = 0.931, p < 0.001 for heart black-blood (BB) imaging; R (2) = 0.993, p < 0.001 for liver imaging). R2* approximately doubled between 1.5 T and 3 T with linear fits for both heart and liver (94, 94 and 105 % respectively). Coefficients of variation for intra- and inter-observer reproducibility, as well as inter-study reproducibility trended to be less good at 3 T (3.5 to 6.5 %) than at 1.5 T (1.4 to 5.7 %) for both heart and liver T2*. Artefact scores for the heart were significantly worse with the 3 T BB sequence (median 4, IQR 2-5) compared with the 1.5 T BB sequence (4 [3-5], p = 0.007). CONCLUSION: Heart and liver T2* and R2* at 3 T show close association with 1.5 T values, but there were more artefacts at 3 T and trends to lower reproducibility causing difficulty in quantifying low T2* values with high tissue iron. Therefore T2* imaging at 1.5 T remains the gold standard for clinical practice. However, in centres where only 3 T is available, equivalent values at 1.5 T may be approximated by halving the 3 T tissue R2* with subsequent conversion to T2*.

The effects of noise in cardiac diffusion tensor imaging and the benefits of averaging complex data.

There is growing interest in cardiac diffusion tensor imaging (cDTI), but, unlike other diffusion MRI applications, there has been little investigation of the effects of noise on the parameters typically derived. One method of mitigating noise floor effects when there are multiple image averages, as in cDTI, is to average the complex rather than the magnitude data, but the phase contains contributions from bulk motion, which must be removed first. The effects of noise on the mean diffusivity (MD), fractional anisotropy (FA), helical angle (HA) and absolute secondary eigenvector angle (E2A) were simulated with various diffusion weightings (b values). The effect of averaging complex versus magnitude images was investigated. In vivo cDTI was performed in 10 healthy subjects with b = 500, 1000, 1500 and 2000 s/mm(2). A technique for removing the motion-induced component of the image phase present in vivo was implemented by subtracting a low-resolution copy of the phase from the original images before averaging the complex images. MD, FA, E2A and the transmural gradient in HA were compared for un-averaged, magnitude- and complex-averaged reconstructions. Simulations demonstrated an over-estimation of FA and MD at low b values and an under-estimation at high b values. The transition is relatively signal-to-noise ratio (SNR) independent and occurs at a higher b value for FA (b = 1000-1250 s/mm(2)) than MD (b ≈ 250 s/mm(2)). E2A is under-estimated at low and high b values with a transition at b ≈ 1000 s/mm(2), whereas the bias in HA is comparatively small. The under-estimation of FA and MD at high b values is caused by noise floor effects, which can be mitigated by averaging the complex data. Understanding the parameters of interest and the effects of noise informs the selection of the optimal b values. When complex data are available, they should be used to maximise the benefit from the acquisition of multiple averages. The combination of complex data is also a valuable step towards segmented acquisitions.

Heterogeneity of Fractional Anisotropy and Mean Diffusivity Measurements by In Vivo Diffusion Tensor Imaging in Normal Human Hearts.

BACKGROUND: Cardiac diffusion tensor imaging (cDTI) by cardiovascular magnetic resonance has the potential to assess microstructural changes through measures of fractional anisotropy (FA) and mean diffusivity (MD). However, normal variation in regional and transmural FA and MD is not well described. METHODS: Twenty normal subjects were scanned using an optimised cDTI sequence at 3T in systole. FA and MD were quantified in 3 transmural layers and 4 regional myocardial walls. RESULTS: FA was higher in the mesocardium (0.46 ±0.04) than the endocardium (0.40 ±0.04, p≤0.001) and epicardium (0.39 ±0.04, p≤0.001). On regional analysis, the FA in the septum was greater than the lateral wall (0.44 ±0.03 vs 0.40 ±0.05 p = 0.04). There was a transmural gradient in MD increasing towards the endocardium (epicardium 0.87 ±0.07 vs endocardium 0.91 ±0.08×10-3 mm2/s, p = 0.04). With the lateral wall (0.87 ± 0.08×10-3 mm2/s) as the reference, the MD was higher in the anterior wall (0.92 ±0.08×10-3 mm2/s, p = 0.016) and septum (0.92 ±0.07×10-3 mm2/s, p = 0.028). Transmurally the signal to noise ratio (SNR) was greatest in the mesocardium (14.5 ±2.5 vs endocardium 13.1 ±2.2, p<0.001; vs epicardium 12.0 ± 2.4, p<0.001) and regionally in the septum (16.0 ±3.4 vs lateral wall 11.5 ± 1.5, p<0.001). Transmural analysis suggested a relative reduction in the rate of change in helical angle (HA) within the mesocardium. CONCLUSIONS: In vivo FA and MD measurements in normal human heart are heterogeneous, varying significantly transmurally and regionally. Contributors to this heterogeneity are many, complex and interactive, but include SNR, variations in cardiac microstructure, partial volume effects and strain. These data indicate that the potential clinical use of FA and MD would require measurement standardisation by myocardial region and layer, unless pathological changes substantially exceed the normal variation identified.

Free-breathing T2* mapping using respiratory motion corrected averaging.

BACKGROUND: Pixel-wise T2* maps based on breath-held segmented image acquisition are prone to ghost artifacts in instances of poor breath-holding or cardiac arrhythmia. Single shot imaging is inherently immune to ghost type artifacts. We propose a free-breathing method based on respiratory motion corrected single shot imaging with averaging to improve the signal to noise ratio. METHODS: Images were acquired using a multi-echo gradient recalled echo sequence and T2* maps were calculated at each pixel by exponential fitting. For 40 subjects (2 cohorts), two acquisition protocols were compared: (1) a breath-held, segmented acquisition, and (2) a free-breathing, single-shot multiple repetition respiratory motion corrected average. T2* measurements in the interventricular septum and liver were compared for the 2-methods in all studies with diagnostic image quality. RESULTS: In cohort 1 (N = 28) with age 51.4 ± 17.6 (m ± SD) including 1 subject with severe myocardial iron overload, there were 8 non-diagnostic breath-held studies due to poor image quality resulting from ghost artifacts caused by respiratory motion or arrhythmias. In cohort 2 (N = 12) with age 30.9 ± 7.5 (m ± SD), including 7 subjects with severe myocardial iron overload and 4 subjects with mild iron overload, a single subject was unable to breath-hold. Free-breathing motion corrected T2* maps were of diagnostic quality in all 40 subjects. T2* measurements were in excellent agreement (In cohort #1, T2*FB = 0.95 x T2*BH + 0.41, r2 = 0.93, N = 39 measurements, and in cohort #2, T2*FB = 0.98 x T2*BH + 0.05, r2 > 0.99, N = 22 measurements). CONCLUSIONS: A free-breathing approach to T2* mapping is demonstrated to produce consistently good quality maps in the presence of respiratory motion and arrhythmias.

Optimal diffusion weighting for in vivo cardiac diffusion tensor imaging.

PURPOSE: To investigate the influence of the diffusion weighting on in vivo cardiac diffusion tensor imaging (cDTI) and obtain optimal parameters. METHODS: Ten subjects were scanned using stimulated echo acquisition mode echo planar imaging with six b-values, from 50 to 950 s·mm(-2) , plus b = 15 s·mm(-2) reference. The relationship between b-value and both signal loss and signal-to-noise ratio measures was investigated. Mean diffusivity, fractional anisotropy, and helical angle maps were calculated using all possible b-value pairs to investigate the effects of diffusion weighting on the main and reference data. RESULTS: Signal decay at low b-values was dominated by processes with high apparent diffusion coefficients, most likely microvascular perfusion. This effect could be avoided by diffusion weighting of the reference images. Parameter maps were improved with increased b-value until the diffusion-weighted signal approached the noise floor. For the protocol used in this study, b = 750 s·mm(-2) combined with 150 s·mm(-2) diffusion weighting of the reference images proved optimal. CONCLUSION: Mean diffusivity, fractional anisotropy, and helical angle from cDTI are influenced by the b-value of the main and reference data. Using optimal values improves parameter maps and avoids microvascular perfusion effects. This optimized protocol should provide greater sensitivity to pathological changes in parameter maps.

In vivo cardiovascular magnetic resonance diffusion tensor imaging shows evidence of abnormal myocardial laminar orientations and mobility in hypertrophic cardiomyopathy.

BACKGROUND: Cardiac diffusion tensor imaging (cDTI) measures the magnitudes and directions of intramyocardial water diffusion. Assuming the cross-myocyte components to be constrained by the laminar microstructures of myocardium, we hypothesized that cDTI at two cardiac phases might identify any abnormalities of laminar orientation and mobility in hypertrophic cardiomyopathy (HCM). METHODS: We performed cDTI in vivo at 3 Tesla at end-systole and late diastole in 11 healthy controls and 11 patients with HCM, as well as late gadolinium enhancement (LGE) for detection of regional fibrosis. RESULTS: Voxel-wise analysis of diffusion tensors relative to left ventricular coordinates showed expected transmural changes of myocardial helix-angle, with no significant differences between phases or between HCM and control groups. In controls, the angle of the second eigenvector of diffusion (E2A) relative to the local wall tangent plane was larger in systole than diastole, in accord with previously reported changes of laminar orientation. HCM hearts showed higher than normal global E2A in systole (63.9° vs 56.4° controls, p=0.026) and markedly raised E2A in diastole (46.8° vs 24.0° controls, p<0.001). In hypertrophic regions, E2A retained a high, systole-like angulation even in diastole, independent of LGE, while regions of normal wall thickness did not (LGE present 57.8°, p=0.0028, LGE absent 54.8°, p=0.0022 vs normal thickness 38.1°). CONCLUSIONS: In healthy controls, the angles of cross-myocyte components of diffusion were consistent with previously reported transmural orientations of laminar microstructures and their changes with contraction. In HCM, especially in hypertrophic regions, they were consistent with hypercontraction in systole and failure of relaxation in diastole. Further investigation of this finding is required as previously postulated effects of strain might be a confounding factor.

Intercentre reproducibility of cardiac apparent diffusion coefficient and fractional anisotropy in healthy volunteers.

BACKGROUND: Diffusion tensor cardiac magnetic resonance (DT-CMR) enables probing of the microarchitecture of the myocardium, but the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) reported in healthy volunteers have been inconsistent. The aim of this study was to validate a stimulated-echo diffusion sequence using phantoms, and to assess the intercentre reproducibility of in-vivo diffusion measures using the sequence. METHODS AND RESULTS: A stimulated-echo, cardiac-gated DT-CMR sequence with a reduced-field-of-view, single-shot EPI readout was used at two centres with 3 T MRI scanners. Four alkane phantoms with known diffusivities were scanned at a single centre using a stimulated echo sequence and a spin-echo Stejskal-Tanner diffusion sequence. The median (maximum, minimum) difference between the DT-CMR sequence and Stejskal-Tanner sequence was 0.01 (0.04, 0.0006) × 10(-3) mm2/s (2%), and between the DT-CMR sequence and literature diffusivities was 0.02 (0.05, 0.006) × 10(-3) mm2/s (4%).The same ten healthy volunteers were scanned using the DT-CMR sequence at the two centres less than seven days apart. Average ADC and FA were calculated in a single mid-ventricular, short axis slice. Intercentre differences were tested for statistical significance at the p < 0.05 level using paired t-tests. The mean ADC ± standard deviation for all subjects averaged over both centres was 1.10 ± 0.06 × 10(-3) mm2/s in systole and 1.20 ± 0.09 × 10-3 mm2/s in diastole; FA was 0.41 ± 0.04 in systole and 0.54 ± 0.03 in diastole. With similarly-drawn regions-of-interest, systolic ADC (difference 0.05 × 10(-3) mm2/s), systolic FA (difference 0.003) and diastolic FA (difference 0.01) were not statistically significantly different between centres (p > 0.05), and only the diastolic ADC showed a statistically significant, but numerically small, difference of 0.07 × 10(-3) mm2/s (p = 0.047). The intercentre, intrasubject coefficients of variance were: systolic ADC 7%, FA 6%; diastolic ADC 7%, FA 3%. CONCLUSIONS: This is the first study to demonstrate the accuracy of a stimulated-echo DT-CMR sequence in phantoms, and demonstrates the feasibility of obtaining reproducible ADC and FA in healthy volunteers at separate centres with well-matched sequences and processing.

Emerging roles for cardiovascular magnetic resonance.

Cardiovascular magnetic resonance (CMR) is a noninvasive imaging tool with high spatial resolution in the absence of ionising radiation. CMR imaging is routine in the functional assessment of coronary lesions and is widely held as the gold standard in myocardial viability imaging. Its unique tissue characterisation capabilities have revolutionised the assessment of the cardiomyopathies and it is the investigation of choice for cardiovascular surveillance imaging. To date its greatest success has been in the management of thalassaemia major, where the ability to detect myocardial iron loading has significantly improved patient survival. In the near future, CMR fibrosis imaging may serve as a risk stratification tool for the cardiomyopathies; and the ability to assess interstitial fibrosis may advance this role into other disease processes. Novel methods of tissue characterisation and emerging technical advances present new avenues for this modality, securing its place as the noninvasive imaging tool of the future.

Characteristics and outcomes of dialysis patients with infective endocarditis.

BACKGROUND: The incidence of infective endocarditis (IE) in dialysis patients is higher than the general population. Dialysis patients who develop endocarditis are thought to have a poorer prognosis than other patients with IE. AIM: To examine the risk profiles, clinical features, and outcomes of patients on dialysis who developed IE in a large cohort. DESIGN AND METHODS: A retrospective analysis of all patients developing IE on dialysis (using the modified Duke criteria) was undertaken between 1998 and 2011. Patients were identified from a prospectively collected clinical database. RESULTS: 42 patients developed IE out of a total incident dialysis population of 1,500 over 13 years. 95% of the patients (40/42) were on long-term haemodialysis (HD) and 5% (2/42) on peritoneal dialysis. Mean patient age was 55.2 years (IQR: 43-69), and mean duration of HD prior to IE was 57.4 months. Primary HD access at the time of diagnosis was an arteriovenous fistula in 35% (14/40), a dual-lumen tunnelled catheter in 55% (22/40), and a dual-lumen non-tunnelled catheter in 10% (4/40). Staphylococcus aureus (including methicillin-resistant S. aureus) was present in 57.1% (24/42). The aortic valve was affected in 42.8% of the patients (18/42), the mitral valve in 30.9% (13/42), and both valves in 9.5% (4/42). 33.3% of the patients had an abnormal valve before the episode of IE. In 21.4% (9/42), valve surgery was performed and mortality was lower in the surgical group compared to the group managed medically during hospitalisation (11.1 vs. 15.2%, p = 0.892), at 3 months (13.1 vs. 19.6%, p = 0.501), and during follow-up (p = 0.207), but this difference did not reach statistical significance. Age >60 years, septic emboli, and methicillin-resistant S. aureus were all adverse prognostic factors. Patients receiving surgery were younger (mean 47.1 ± 14.4 years vs. 57.4 ± 14.3, p = 0.049) and less likely to be infected with S. aureus (surgery 33.3% vs. antibiotics 63.6%, p = 0.046). CONCLUSION: This is one of the largest reported series of IE in dialysis patients. The incidence of IE remains high and the prognosis poor in dialysis patients, although patients selected for early valve surgery have good 1-year survival.

Reproducibility of in-vivo diffusion tensor cardiovascular magnetic resonance in hypertrophic cardiomyopathy.

BACKGROUND: Myocardial disarray is an important histological feature of hypertrophic cardiomyopathy (HCM) which has been studied post-mortem, but its in-vivo prevalence and extent is unknown. Cardiac Diffusion Tensor Imaging (cDTI) provides information on mean intravoxel myocyte orientation and potentially myocardial disarray. Recent technical advances have improved in-vivo cDTI, and the aim of this study was to assess the interstudy reproducibility of quantitative in-vivo cDTI in patients with HCM. METHODS AND RESULTS: A stimulated-echo single-shot-EPI sequence with zonal excitation and parallel imaging was implemented. Ten patients with HCM were each scanned on 2 different days. For each scan 3 short axis mid-ventricular slices were acquired with cDTI at end systole. Fractional anisotropy (FA), mean diffusivity (MD), and helix angle (HA) maps were created using a cDTI post-processing platform developed in-house. The mean ± SD global FA was 0.613 ± 0.044, MD was 0.750 ± 0.154 × 10-3 mm2/s and HA was epicardium -34.3 ± 7.6°, mesocardium 3.5 ± 6.9° and endocardium 38.9 ± 8.1°. Comparison of initial and repeat studies showed global interstudy reproducibility for FA (SD = ± 0.045, Coefficient of Variation (CoV) = 7.2%), MD (SD = ± 0.135 × 10-3 mm2/s, CoV = 18.6%) and HA (epicardium SD = ± 4.8°; mesocardium SD = ± 3.4°; endocardium SD = ± 2.9°). Reproducibility of FA was superior to MD (p = 0.003). MD was significantly higher in the septum than the reference lateral wall (0.784 ±0.188 vs 0.714 ±0.155 ×10-3 mm2/s, p <0.001) [corrected]. Septal HA was significantly lower than the reference lateral wall in all 3 transmural layers (from -8.3° to -10.4°, all p < 0.001). CONCLUSIONS: To the best of our knowledge, this is the first study to assess the interstudy reproducibility of DTI in the human HCM heart in-vivo and the largest cDTI study in HCM to date. Our results show good reproducibility of FA, MD and HA which indicates that current technology yields robust in-vivo measurements that have potential clinical value. The interpretation of regional differences in the septum requires further investigation.