Numerous investigators have suggested that woman are particularly prone to develop an exaggerated LV hypertrophy (LVH) response to increased developed pressure as compared to men. This has been best exemplified in both HTN and aortic stenosis (AS) states and has been proposed euphemistically as 'exuberant hypertrophy'. This reference implies that there is an inappropriate physiologic amplification to the typical and necessary hypertrophic response for any given blood pressure/afterload experienced by the LV. Furthermore, it suggests that there is a divergent response at the gene level to explain this phenomenon. The implications for this are vast, potentially calling for distinct sex-based clinical treatment programs. The societal ramifications for differential therapy are immense as our resources are limited. On the other hand, the majority of the inferences of this dichotomized observation have stemmed from 2D Echocardiography and consequently may be artifactual if evaluated in a 3D CMR manner.We hypothesize that 'exuberant hypertrophy' is a misnomer and that after aortic valve replacement (AVR) there will be no sex difference in the manner or rate in which LVH regresses following afterload relief.Following initial recruitment of 35 patients for a longitudinal 2-year CMR study, a series of patients who were alive and available were specifically contacted and re-recruited for follow-up up to 4 years from their initial AVR. All patients underwent an additional CMR for evaluation of 3D volumetrics including LV mass and EF. Using Simpson's rule, contiguous 8 mm slices were acquired via SSFP imaging and underwent LV endocardial and epicardial manual contouring . Pre and post-AVR LV mass and EF were compared and stratified for sex. A 'p' value of <0.05 was considered statistically significant.2, p = NS). However, baseline EF was dissimilar between woman and men . Following AVR, in absolute or relative terms, LV mass index regression was not different between the sexes ,  patients were available for CMR at 3 ± 1 yrs out to 4 years at follow-up post-AVR and successfully underwent CMR. Woman  and men ; (p < NS for both) were imaged. Baseline LV mass index was not either increased in females nor different between woman and men  are nullified. This finding may restore the notion that there are neither phenotypic nor likely genotypic alterations in the LV response to pressure afterload in woman vs. men.While conceptually intriguing and highly controversial, the sex-based differences of exaggerated LVH formation in response to pressure afterload that are based substantially on 2D echocardiographic acquisitions appear to be


Mean medullary FA proved to be a significant predictor for tubular atrophy (p < 0.001), while cortical T1 appeared as a significant predictor of interstitial fibrosis (p = 0.003). Conclusion: Cortical T1, medullary FA, and FA CMD might serve as new imaging biomarkers of renal function and histopathologic microstructure.Background: Magnetic resonance relaxometry (MRR) offers highly reproducible pixel-wise parametric maps of T1 and T2 relaxation times, reflecting specific tissue properties, while diffusion-tensor imaging (DTI) is a promising technique for the characterization of microstructural changes, depending on the directionality of molecular motion. Both MMR and DTI may be used for non-invasive assessment of parenchymal changes caused by kidney injury or graft dysfunction. Methods: We examined 46 patients with kidney transplantation and 16 healthy controls, using T1/T2 relaxometry and DTI at 3 T. Twenty-two early transplants and 24 late transplants were included. Seven of the patients had prior renal biopsy . Results: Compared to healthy controls, T1 and T2 relaxation times in the renal parenchyma were increased after transplantation, with the highest T1/T2 values in early transplants (T1: 1700 ± 53 ms/T2: 83 ± 6 ms compared to T1: 1514 ± 29 ms/T2: 78 ± 4 ms in controls). Medullary and cortical ADC/FA values were decreased in early transplants and highest in controls, with medullary FA values showing the most pronounced difference. Cortical renal T1, mean medullary FA and corticomedullary differentiation (CMD) values correlated best with renal function as measured by  Kidney transplantation is currently considered the best available therapy for patients with end stage renal disease . HoweverAt present, diagnosis of renal impairment is predominantly based on serum creatinine (sCr) and the level of urine output . HoweverRecent years have witnessed a growing interest in quantitative magnetic resonance imaging (MRI) of the kidney . MagnetiAnother promising functional imaging technique for renal transplants is diffusion-weighted imaging (DWI). DWI enables measurement of the Brownian motion of water in the extracellular space, whereby the quantitative mean apparent diffusion coefficient (ADC) may be calculated from diffusion-weighted images. Going beyond that, information from DTI also contains the directionality of molecular motion. This is important for kidney imaging because anatomical structures such as vessels and tubules show a radial orientation, causing anisotropy. Directionality of molecular motion may be quantified by fractional anisotropy (FA). Prior research suggests that DWI is particularly sensitive to changes in the renal interstitium, such as renal fibrosis, cellular infiltration or edema . For reneGFR was investigated.The present study aimed to evaluate both quantitative T1 and T2 and cortical and medullary FA values as functional MRI biomarkers in patients short and long term after kidney transplantation to investigate potential acute and chronic post-transplantation kidney damage, using a field strength of 3 Tesla. Furthermore, a correlation of renal T1, T2, and DTI parameters with This prospective study was approved by the local Institutional Review Board, whereby written informed consent was obtained from all participants in advance (reference number EA1/028/19). Between January 2019 and January 2020, 62 subjects received an MRI examination of the abdomen at a field strength of 3 T . The study population consisted of 22 early transplants , 24 late transplants (at least 3 months since transplantation) , and 16 controls with healthy kidney function , defined by an individual eGFR above 60. All subjects agreed to the participate in the study and had no contraindications against MRI. One patient was excluded due to insufficient image quality with multiple breathing artifacts. In the group of early transplants, sCR was determined the day before and after surgery, the day of the MRI examination, and 3 months after surgery. eGRF was used to estimate kidney function, based on the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula .In 7 patients, a prior percutaneous biopsy within a year of the MRI had been performed . For these patients, Banff scores  for tubular, vascular, and glomerular involvement were obtained from the histopathologic report and then analyzed. The Banff scores included the lesion scores ct for tubular atrophy, ci for interstitial fibrosis, g for glomerulitis, i for interstitial inflammation, and ti for total inflammation.All examinations were performed using a 3-T clinical scanner  with an 18-channel body coil combined with a 32-channel spine coil and an automatic selection of coil elements. The patients received an MRI of the abdomen with sequences for anatomical imaging, including a half Fourier singleshot turbo spin-echo (HASTE) sequence with and without fat saturation and a Dixon sequence. HASTE is a single-section T2-weighted sequence with image acquisition in less than 1 s, which allows for breathing independent acquisition of high-resolution T2-weighted images. It is based on a single-shot technique to acquire sufficient data for the image from a single time of repetition. The short acquisition time makes it less susceptible to motion, which is especially helpful for abdominal imaging . The DixThe T1 relaxometry technique is based on the acquisition of single-shot TrueFISP images with different inversion times (TI) after an initial inversion pulse. The acquisitions are assigned to the same cardiac phase, which allows a pixel-based assessment of the T1 value in the kidney. Each slice for T1 and T2 mapping was acquired within one breath-hold. Refer to T1 and T2 maps were calculated automatically on a pixel-by-pixel basis. The resulting pixel-by-pixel maps had customized color coding with bright colors corresponding to longer and dark colors to shorter relaxation times. T1 and T2 maps are presented along with a color bar, corresponding to relaxation times between 0 and 2000 ms for T1 mapping and relaxation times between 0 and 120 ms for T2 mapping. ADC and FA maps were also calculated inline, with calculation of FA parametric maps to assess the degree of diffusion anisotropy. FA values enable a quantitative measurement of diffusion anisotropy on a scale from 0 (isotropic) to 1 (fully anisotropic).In early transplants, MRI was performed 3–14 days after kidney transplantation. For late transplants, MRI was performed in patients within 0.5–13 years since transplantation.In a small subgroup of 6 freshly transplanted patients, two MRI measurements were performed, the first between the Postoperative Days 4 and 6 and the second between Postoperative Days 11 and 14.2, the maximum size was 88.3 mm2, and the minimum size was 32.1 mm2. The pixel range for the cortex and medullary measurements was 612–2412 per measurement of the renal cortex area (5–134 per ROI) and 612–1584 per measurement of the renal medulla (5–88 per ROI). Measurements were averaged over two observers and then mean and standard deviations were calculated. In patients with diminished corticomedullary differentiation (CMD), anatomical T1 and T2 images in coronal planes were used for anatomical reference. CMD was calculated for T1, T2, ADC and FA values.All images were analyzed using PACS workstations . Two radiologists performed the image analysis, blinded to the clinical information. They randomly evaluated T1, T2, ADC, and FA maps in two different reading sessions. For each patient, six ROIs were drawn in three slices for each cortex and medulla, a total of 18 ROIs for the cortex and 18 ROIs for the medulla cf. . The ROIt-tests were used to assess the differences in means for continuous variables. Bar plots with error bars representing one standard deviation were used to represent the distribution of the mean T1 and T2 values in the different groups. A linear regression analysis was used to assess relationships between two measurements. A ROC analysis was performed to establish the suitability of different relaxometry and DTI parameters for the assessment of high and severe renal insufficiency. A logistic regression analysis was performed to assess the association between biopsy results and functional MR parameters. A p-value < 0.05 was considered statistically significant. Correction for multiple testing was performed based on the Holm–Bonferroni method [All variables are given as mean values ± standard deviations. Student i method . StatistA total of 46 patients and 16 controls met the eligibility criteria, with a mean age of 52.9 ± 11.9 years for the transplanted patients and of 59.9 ± 14.4 years for the controls. p > 0.05).The average time interval between surgery and MRI was 6.8 ± 3.4 days for the early transplants and 5.5 ± 5.1 years for the late transplants. Kidney size was not significantly different between allografts with normal and decreased renal function (p < 0.001) and controls (p < 0.001) (cf. p = 0.041) as well as the differences between early transplants and controls (p < 0.001) and between late transplants and controls (p = 0.003) were significant. As a result of the greater increase in cortical T1 relaxation times compared to medullary T1 relaxation times, the CMD was most lowered in early transplants (347.8 ± 119.3 ms), compared to late transplants (389.6 ± 117.5 ms) and controls . However, these differences in T1 CMD were not significant. In addition, there were no significant differences depending on age or gender. The highest mean cortical T1 relaxation times were measured in early transplants with 1700 ± 53 ms, followed by late transplants with 1615 ± 47 ms and controls with 1514 ± 29 ms. All differences between the groups were significant for cortical T1, with early transplants showing higher T1 relaxation times compared to late transplants (p < 0.001) and between early transplants and controls (p < 0.001) were significant. In addition, the difference between late transplants and controls reached significance level (p < 0.001). Correspondingly, the CMD was most lowered in early transplants (15.3 ± 7.8 ms), compared to late transplants  and controls . Only the T2 CMD between early transplants and controls reached significance (p = 0.036). Similar to T1 relaxometry, the highest cortical T2 relaxation times were measured in early transplants with 83 ± 6 ms, followed by late transplants with 82 ± 8 ms and controls with 78 ± 4 ms. Compared to T1 relaxometry, the differences between the groups were smaller between the groups and differences in medullary T2 relaxation times were more pronounced than differences in cortical T2 relaxation times. For T2 medullary relaxation times, the differences between early and late transplants (−6 mm2/s), followed by late transplants . Early transplants demonstrated the lowest ADC values  (cf. p < 0.001). For cortical FA, differences between all groups were significant .Mean ADC values from the renal cortex and medulla were highest in controls  cf. . DiffereeGFR on the day of the MRI examination, whereas the CMD showed a positive correlation with eGFR. While the strength of correlation between cortical T1 and eGFR was moderate (r = −0.63), it was weaker for T1 CMD, and eGFR (r = 0.47). Regarding T2 parameters, all parameters only showed weak to negligible correlations with renal function, whereby the highest correlation was between medullary T2 and eGRF with a correlation coefficient of −0.35. The best correlation between eGRF and FA parameters was found for mean medullary FA values  as well as FA CMD . Correlations between eGFR and cortical FA as well as ADC parameters were significant, but weak (r between −0.14 and 0.35). eGFR.Cortical T1 relaxation times negatively correlated with eGFR below 30 mL/min) and severe renal insufficiency (eGFR below 15 mL/min), we found that the area under the ROC (AUC) was highest for cortical T1 (AUC of 0.91 or 0.90) and medullary FA (AUC of 0.94 or 0.91) (cf. eGFR below 30 mL/min or 15 mL/min.In a receiver operating characteristic curve (ROC) analysis to establish the suitability of different MRR and DTI parameters for the assessment of high (.91) cf. . CorticaBy comparison, for T1 CMD the AUCs were 0.71 to distinguish an eGRF below 30 and 0.74 to differentiate an eGRF below 15 from better functioning kidneys. For medullary T2, the AUCs were 0.71 to distinguish an eGRF below 30 or below 15 from better functioning kidneys. Cortical FA reached an AUC of 0.67.p < 0.001), while cortical T1 appeared as a significant predictor of interstitial fibrosis (p = 0.003).Seven biopsies were available for analysis . In a logistic regression analysis, mean medullary FA proved to be a significant predictor for tubular atrophy  in a small number of available biopsies. Hence, multiparametric MRI might enable the non-invasive assessment of renal tissue changes following renal transplantation.To date, the inconsistency of imaging protocols remains an ongoing challenge for multiparametric renal MRI, which requires standardization. Recently, recommendation papers have been published for both renal relaxometry and DWI ,21. The 2, and for more than 12 diffusion directions [2. While a minimum of two b values is enough to reach a stable diffusion signal, including more b values in the acquisition protocol allows for a more precise description of diffusion signal decay and could improve the robustness of DTI [n = 64), it can be assumed that this lowered the variability for the estimation of FA [Recent recommendations for the clinical translation of renal diffusion-weighted MRI comprise normal hydration of the patients, single shot EPI, oblique coronal orientation, matrix >128, in-plane resolution of 2–3 mm, full kidney coverage, spectral attenuated inversion recovery fat saturation, TE <100, distortion correction, unilateral registration, if possible, and metric statistics reporting with mean, median, standard deviation, and ROI size . Regardirections . Manual rections . Again, s of DTI ,22. Thers of DTI . As we con of FA .In the context of T1 and T2 relaxometry, animal research suggested an association of T2 relaxation times with renal edema after interruption of blood flow and that increased water content is an important cause for the prolongation in renal T1 relaxation times ,25. FrieFor DWI, Wang et al. found that functional ADC measurements correlated with kidney allograft interstitial fibrosis. In the context of DTI, studies in human kidneys demonstrated higher FA values in the renal medulla compared to the renal cortex ,30. A ren = 7). Future studies on multiparametric MRI should therefore focus on the correlation of quantitative MR parameters with histopathological results as an indicator for clinical outcomes. As a first step towards larger diagnostic and prognostic studies, the repeatability of multiparametric kidney MRI has to be determined [Even though we found significant correlations between T2 and ADC parameters and eGFR, these correlations were comparatively weak. In addition, for these parameters, we did not observe any significant correlations with histopathology. Therefore, based on our results, T2 relaxometry appears inferior to T1 relaxometry for the evaluation of renal function as measured by eGFR, while—in agreement with Bane et al.—DWI seemed inferior to DTI. However, it has to be pointed out that no recommendations for the most suitable relaxometry or diffusion parameters to predicted outcomes of biopsies or to identify high- or low-risk groups can be derived from the results of the present study. Obviously, the strong correlation with eGFR observed for T1- and FA-derived parameters does not allow for an estimate of renal function superior to eGFR. The number of available biopsies, all taken from malfunctioning kidney, was very low (termined . Intersetermined . Howevern = 7) and the time intervals between biopsies and MRI varied. In addition, the longest time interval between biopsy and MRI was nearly six months, which could make the comparison to MRI unreliable. To this end, the observed correlations between histology and MRI must be viewed critically. Future studies should therefore evaluate to what extent MRR parameters could complement the laboratory values and if they correlate with histology.Apart from this, the present study has some further limitations: First, there is no long-term follow up, which prevents insight into the detailed prognostic value of T1/T2 relaxometry and DTI. Another aspect is that MOLLI was performed with cardiac triggering. Although MOLLI with cardiac triggering is frequently used for cardiac imaging, the recent consensus-based recommendations by Dekkers et al. instead proposed a fixed interval of 1 ms between measurements for renal imaging . BesidesIn summary, quantitative T1 and T2 relaxation times are most increased, while ADC and FA values are most decreased in early transplants. They appear to remain, respectively, higher (T1 and T1) or lower (ADC and FA) in the long term compared to healthy subjects, suggesting permanent underlying tissue changes. Out of all functional parameters, cortical T1 and medullary FA showed the best correlation with eGFR. In a small number of available biopsies, they were also associated with interstitial fibrosis (T1) and tubular atrophy (FA). Consequently, cortical T1 and medullary FA might serve as new imaging biomarkers of renal function and histopathologic microstructure.


The use of cardiovascular magnetic resonance imaging left atrial late gadolinium enhancement (LA LGE) is increasing for fibrosis evaluation though the use is still limited to specialized centres due to complex image acquisition and lack of consensus on image analyses. Analysis of LA LGE with image intensity ratio (IIR)  provides an objective method to obtain quantitative data on atrial fibrosis. A threshold between healthy myocardium and fibrosis of 1.2 has previously been established in 3T scans. The aim of the study was to reaffirm this threshold in 1.5T scans. LA LGE was performed using a 1.5T magnetic resonance scanner on: 11 lone-AF patients, 11 age-matched healthy volunteers (aged 27–44) and 11 elderly patients without known history of AF but varying degrees of comorbidities. Mean values of IIR for all healthy volunteers +2SD were set as upper limit of normality and was reproduced to 1.21 and the original IIR-threshold of 1.20 was maintained. The degree of fibrosis in lone-AF patients [median 9.0% (IQR 3.9–12.0)] was higher than in healthy volunteers [2.8% (1.3–8.3)] and even higher in elderly non-AF . The previously established IIR-threshold of 1.2 was reaffirmed in 1.5T LA LGE scans. Patients with lone AF presented with increased degrees of atrial fibrosis compared to healthy volunteers in the same age-range. Elderly patients with no history of AF showed significantly higher degrees of fibrosis compared to both groups with younger individuals.The online version of this article (10.1007/s10554-019-01728-0) contains supplementary material, which is available to authorized users. The clinical demand for cardiac magnetic resonance imaging (CMR) and the corresponding scientific developments have been expanding during the past 20 years . Late gaDespite its many promising possibilities, LA LGE has remained a method reserved for highly specialized centres and previous studies have reported both positive , 14, 15 The image intensity ratio (IIR) analysis method of LA LGE uses the mean blood volume intensity as reference , 25. By The aim of this study was to reproduce the LA LGE IIR threshold found at 3T for healthy atrial myocardium in healthy volunteers scanned on a 1.5T MRI scanner.A total of 33 participants were included for the study: 11 healthy volunteers, 11 patients with lone paroxysmal atrial fibrillation (AF) and 11 elderly patients.The group of healthy volunteers served as reference for healthy tissue and were used for calculating the image intensity ratio (IIR) threshold at 1.5T. This group consisted of 11 healthy volunteers, age-matched to the below-mentioned lone AF patients. The healthy volunteers had no history of heart disease or other health conditions and did not receive prescription medication.Two patient groups were included for verification of the threshold obtained: 11 patients with lone paroxysmal atrial fibrillation aged less than 45 years of age and no prior ablations and 11 elderly patients (minimum 70 years of age) with no history of AF but with various degrees of known diabetes mellitus, hypertension, congestive heart disease and/or previous stroke.Exclusion criteria for all included participants were glomerular filtration rate < 60 mL/min, claustrophobia, known gadolinium allergy and implanted ferromagnetic metals.All included participants were scanned for research purposes and provided written informed consent prior to inclusion. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the local ethics committee of the Capital Region of Denmark (Protocol Number H-1-2011-044 and H-4-2013-025).A 1.5T MRI scanner  with an 18-channel body coil was used to scan all included patients and healthy volunteers at Rigshospitalet, Copenhagen, Denmark. After scout sequences, long axis cine images  images were acquired for planning of a short axis stack and aid in delineation of chambers. An axial cine stack ranging from the basis to the aortic arch and a short axis cine stack covering the entire left ventricle were obtained for measurement of left atrial and left ventricular volumes, respectively  × 360 adjusted for each patient; matrix size [182–224) × (138–224)] at 10–15 s end-expiratory breath-holds).The left atrial late gadolinium enhancement (LA LGE) scan was performed 20 min after bolus injection of 0.2 mmol/kg gadobutrol , with a maximum of 15 mmol in total . The LA 42 . On short axis cine images left ventricular (LV) end-diastolic and end-systolic phases were traced manually at the endo- and epicardial border. Left ventricular outflow tract (LVOT) was included in the blood pool; papillary muscles were excluded, using windowing for the endocardial border detection. Epicardium was delineated in both phases to compare left myocardial mass in end-diastole and end-systole. Left atrial (LA) volumes were traced manually on axial cine images. Left atrial appendage was included in left atrial volume. Minimum and maximum volumes were indexed to body surface area.Volumetric measurements were performed in CVI® image post-processing software . On all axial images the atrial blood pool was initially segmented and atrial wall was interpolated automatically into a 3D shell, which was manually adjusted. To avoid epi- or endocardial artefacts or partial volume effects, the software was set to create a single mid-myocardial layer, which was manually adjusted according to MRI images to represent mid-atrial wall. Inflow artefacts were excluded. Pulmonary veins and mitral valves were excluded for fibrosis analyses. Pixel intensities were calculated automatically and shown on the 3D shell. Atrial wall pixel intensities and mean blood pool intensity were exported from ADAS ®. Image intensity ratio (IIR) values of all atrial wall pixels were calculated as atrial wall pixel intensity divided by mean blood pool intensity) . Intraclass correlation coefficient (ICC) was evaluated (good correlation was defined as ICC > 0.70). Bland–Altman plots were constructed and visually inspected for bias or proportional error. P-values < 0.05 were considered statistically significant. All analyses were performed in SPSS Statistics .Continuous variables are presented as mean ± SD or median (interquartile range) and compared with one-way ANOVA/Kruskal–Wallis test. For pairwise comparisons, Table In total, 308,877 pixel points were registered from healthy controls, 277,666 from lone AF patients and 314,393 from elderly non-AF patients and plotted as histograms  threshold was extracted from healthy volunteer data (IIR mean + 2 SD) which was 1.21. When separating the healthy controls into an older and a younger fraction according to mean age, the IIR for < 37 (n = 6) and > 37 years (n = 5) were 1.22 ± 0.07 versus 1.21 ± 0.06 (p = 0.92).The small deviation from the threshold set by Benito et al.  , lone-AF patients at 9.0% (3.9–12.0) and reaching the highest median value in elderly non-AF patients at 20.1% (10.2–35.8)  and intra-observer ICC = 0.995 . Bland–Altman plots are depicted in Fig. S1. Mean difference for inter-observer agreement was − 1.7 limits of agreement  and for intra-observer − 1.0 .The present study verifies the use of the image intensity ratio (IIR) threshold value of 1.20 distinguishing healthy from fibrotic atrial myocardium in 1.5T LA LGE scans. This threshold value has previously been established in 3T scans on healthy volunteers  but neveThe IIR analysis method was initially introduced by Khurram et al., who defined two IIR thresholds based on electroanatomic mapping (EAM): One at 0.97 distinguishing healthy myocardium from diffuse fibrosis and the other at 1.61 distinguishing diffuse fibrosis from dense fibrosis . These tCMR determination of LA LGE seems very promising , 31, 32.Increased degree of native pre-ablation atrial fibrosis has been associated with age , 32, 36,Our results show that patients with lone AF have higher degrees of atrial fibrosis compared to age-matched healthy volunteers. These patients have no detectable structural heart disease and all included patients had paroxysmal AF, possibly the form with the least electrical and structural remodelling, which was also reflected by similar findings in other CMR parameters. It should especially be noted that atrial dimensions were similar in all three groups. This suggests that AF itself is associated with increased degree of fibrosis independently of structural remodelling, which is also supported by other studies , 36, 39.The fibrotic atrial cardiomyopathy (FACM) concept of Kottkamp  explainsThe study is based on a relatively small number of patients and healthy volunteers but nevertheless provides a reproduction of the same IIR threshold value as found by Benito et al. . In geneFibrosis is a dynamic process stretching from initial inflammation and ultimately potentially development of scar, i.e. stable fibrotic tissue. As in all LGE studies, there is the possibility that visualised LGE in fact reflects early inflammatory processes/oedema in the myocardium and not stable fibrotic tissue , hence eWe decided to only test the threshold distinguishing between healthy and fibrotic atrial wall since this separation is clinically relevant and we have found no studies suggesting further value of two thresholds.The thickness of the atrial wall is close to the resolution of CMR and hence especially for thin in-plane structures the 3D-acquisition can provide low accuracy and some degree of partial volume effects may be unavoidable.While some studies find no correlation between age and increased fibrosis , 26, 38 With regards, to the elderly non-AF population, there is the possibility that they have experienced asymptomatic AF episodes.In 1.5T LA LGE scans on healthy volunteers we found an IIR threshold of 1.21 for healthy versus fibrotic tissue which is similar to the previously found threshold of 1.20 in 3T scans. The IIR threshold between healthy and fibrotic atrial myocardium of 1.2 can thus be used for both field strengths.Using the IIR threshold of 1.20, we found increased degrees of left atrial fibrosis in patients with lone paroxysmal AF compared to healthy controls in the same age-range. Elderly patients with no known history of AF but known diabetes mellitus, hypertension, congestive heart disease and/or previous stroke had significantly higher degrees of left atrial fibrosis than both groups of younger individuals.Supplementary material 1 (DOCX 17 kb)Below is the link to the electronic supplementary material.


Radiolucent lines on immediate postoperative cemented acetabular component radiographs between the PMMA bone cement mantle and bone are an indicator of an increased risk of early loosening. The cause of these lines has yet to be identified. Thermal and chemical necrosis, fluid interposition and cement shrinkage have all been suggested in the literature. The aim of the study reported here was to take an engineering approach – eliminating confounding variables present during surgery – to quantify the size of the interstice created by cement shrinkage when a 50 mm diameter flanged acetabular cup is implanted in a model acetabulum with a 52 mm hemispherical bore under controlled conditions using vacuum and non-vacuum mixed cement. Irrespective of the mixing method used, a significant interstice was created between the bone cement and the mock acetabulum. When the cement was mixed under vacuum the interstice created between the mock acetabulum and the cement mantle was 0.60 mm ± 0.09 mm; when the cement was mixed under non-vacuum conditions the interstice created was 0.39 mm ± 0.15 mm. Possible explanations for radiolucent lines are discussed. This, in turn, creates a layer of soft tissue which can be seen on radiographs as a radiolucent line.2 However, this long-term bone resorption process does not explain reports of radiolucent lines on immediate post-operative radiographs around the cement mantle of acetabular cups.38 Authors have suggested these may develop due to thermal necrosis,917 chemical necrosis,19 fluid imposition,2024 and cement shrinkage.1426Cemented total hip arthroplasty (THR), according to NJR statistics, has the lowest rate of revision at all time points after surgery.27 Polymerisation results in an increase in molecular density and therefore volume shrinkage. The reaction is exothermic so the cement mantle will generate and expel heat; this will cause thermal expansion of the cement mantle during polymerisation and subsequent shrinkage as the temperature falls to that of the surroundings.Most bone cements used for acetabular cup fixation are based on PMMA (polymethyl-methacrylate). The cement comes as two components: a powder, which is primarily ground PMMA and a liquid which is primarily MMA monomer. When the two components are mixed a polymerisation reaction starts which continues until full cure and rigidification.9 In a review paper, Lewis reported that the majority of studies show that most cements, excluding Palacos R, show a significant increase in fatigue strength when mixed under vacuum compared to when mixed under non-vacuum conditions.28 In his own study Lewis reported that for a given cement, vacuum mixing significantly improves the fatigue performance.29 Vacuum mixing of bone cement reduces the porosity of the cement mantle created and therefore increases the amount of shrinkage from 2% to 5% for hand mixed cement14 to 3%–6% for vacuum mixed cement.30 Haas et al. reported that preventing the creation and expansion of pores within the cement through vacuum mixing may contribute to this increased extent of shrinkage.14 Bone cement does not form adhesive bonds but rather relies on mechanical interlock with bone trabeculae for fixation.32 Any deformation due to cement shrinkage after the cement has been formed to the bone may result in a reduction of the quality of the fixation between the bone and the bone cement. A key concern regarding shrinkage of bone cement is that any interstices created between cement and bone provides migration paths for wear debris from the articulating bearing to penetrate the interface and cause particulate-mediated osteolysis and subsequent aseptic loosening.33 A study that uses data from the Swedish national hip arthroplasty registry reports that risk of failure is initially increased due to vacuum mixing. However, the risk of failure gradually reduces and risk of revision when compared to open bowl hand mixing is lower after eight years.34Historically, vacuum mixing was introduced into the standard cement preparation methodology to reduce the porosity of the cement mantle as it was believed that pores act as crack propagation sites and therefore can significantly weaken the cement.This paper focuses on cement shrinkage between the acetabulum and the cement mantle.No studies were found that attempt to quantify the interstice created between the cement mantle and acetabulum during cemented acetabular implantation.In this study three questions were asked:Is there significant shrinkage of the bone cement mantle after cemented cup implantation?Does vacuum mixing of the bone cement result in an increased bone cement mantle shrinkage?Is the shrinkage uniform across the whole acetabulum?The model acetabulum was manufactured from stainless steel 304. A 52 mm diameter hemispherical bore was reamed into the steel, a typical diameter to which the acetabulum is reamed . A coordA flanged acetabular cup design was chosen and manufactured from HXLPE (highly-crosslinked polyethylene), which had an external diameter of 50 mm .A Depuy Smartseal acetabular pressuriser  was used for pressurisation of the cement. The pressuriser consists of a silicone spherical segment. When force is applied it is designed to seal off the acetabulum cavity with the cement still inside, thus pressurising the cement .The assembled rig, consisting of mock acetabulum and pressuriser  was mounAll equipment that was manufactured had a tolerance of ± 0.05 mm. Due to the design of the rig this means that the force will be applied within 0.25 mm of the centre of the acetabulum cavity.35 Mould release spray  was used to ensure that the cement mantle could be removed from the model acetabulum.All equipment used for the bone cement shrinkage experiments was kept at room temperature. Experiments were performed between 20.5°C and 23°C which is slightly outside the range defined by ISO 5833 (22°C–24°C) and the relative humidity was between 45% and 50% which is within ISO 5833 recommendations.35 Doughing time is defined as the time at which fibers stop being created between a surgical glove and the cement mass after touching.35 For vacuum mixing, the cement was mixed using a Hivac Bowl  under a 0.4 bar (absolute) vacuum. The cement was mixed for 1 minute under vacuum then removed to test whether the cement had reach the doughing time.The bone cement was mixed by hand in an open bowl in five experiments and mixed under vacuum in five other experiments. For the open bowl, non-vacuum mixed conditions the cement was mixed in a glass bowl and mixed with an inert polyethylene spatula by hand at around 1 Hz until homogeneous and then left to rest until the cement past the doughing time.35 In the experiment the orientation of the acetabulum was orthogonal to the direction of loading. Although during surgery the cup is implanted at an angle of 40° to the transverse plane of the body the force applied by the surgeon is still orthogonal to the plane of the cup face and therefore identical to the laboratory setup described here.For both mixing conditions the cement was inserted into the model acetabulum when it had reached the doughing time and pressurised with a Depuy Smartseal pressuriser for 100 s at 100 N .35 In thAfter the pressuriser was removed, the acetabular cup was inserted into the cement mantle and a force of 50 N was applied. The force was removed after the cement had fully cured .3639 The timings were determined using the cement properties that can be found in the manual for the cement used.In the cited literature, the force applied during pressurisation and cup implantation were done by hand, this produced unrepeatable results. The forces used in this study were finalised after preliminary tests showed that the pressures produced at the surface of the acetabulum with this methodology were comparable to other studies in the literature.The experiment was concluded once the cement mantle had returned to room temperature, after this the cement mantle was removed from the acetabulum. The diameter of the resulting cement mantle was measured using a Mitutoyo Quickscope. The mantle was secured in the microscope and eight to fifteen coordinates were taken over the circumference of the mantle. A script was used to calculate the diameter of the mantle using the circumferential coordinates. This was repeated five times for each mantle. The precision of the coordinates taken were 0.0025 mm. This technique was then performed separately for the rim and the pole of the cement mantle to investigate whether the shrinkage was uniform. The rim was defined as the top 45° from the opening of the cavity (zone I and III) and the rim was all of the mantle below this (zones II) as this criterion was used by Delee and Charnley to describe the three zones of the acetabulum .The measurement technique described was validated as follows: A spherical test piece of known diameter was measured, and the result was found to be within 0.05 mm of the true value. In addition, a coordinate measuring machine (CMM) was used to check the Quickscope measurements and this also found the result to be within 0.05 mm. Therefore, the Quickscope method was satisfactory for the level of accuracy required.Two cement mantles from each mixing condition were sectioned so that the porosity and the mantle thickness could be measured. As the cement-bone interface was the focus of this study the internal diameter was not measured. The thickness was determined using a Vernier caliper; 10 measurements for the rim and the pole were taken and the results averaged. The porosity, reported as a ratio of pore area to total area, was determined using images taken on a Hitachi TM3030 scanning electron microscope  (SEM). Eight images were taken in total for each mantle: one in each quadrant of the sectioned area . This wat-test was used to determine whether there was a significant difference between compared variables shown in the table below , this may alter the extent of the cement mantle shrinkage. The heating due to polymerisation would also cause changes to the dimensions of the mock acetabulum and therefore alter the dimensions of the resulting cement mantle. A steel manufacturer states that stainless steel has a thermal expansion coefficient of between 16 and 18 ×1046 Ideally, during implantation the acetabulum should be dry to maximise interface strength and therefore the effects of swelling on the volume of the cement mantle will occur sometime after implantation.For this study the acetabulum model was dry, N’Diaye et al. found that PMMA bone cement experiences significant swelling due to water absorption, this swelling may reduce some of the shrinkage effects observed in this study.The Shimadzu used to insert the acetabular cup was force controlled, this is partially representative of a real surgery in that the surgeon uses a combination of instinctive force control and estimated final position required; in our model this resulted in a slightly thicker cement mantle at the pole. Some preliminary studies were undertaken to try and position the cup so there was a uniform cement mantle, but due to the complex system dictating the viscosity of the cement, this methodology was not reliably repeatable.Data for one type of cement has been presented in this current study. Future work should be done to investigate whether the results reported here apply to other types of cement.The diameter of the acetabular cup used was 2 mm larger than that which is generally recommended by surgeons and manufactures. The effect of cup size on the size of the interstice created between the cement mantle and bone, and the pressure at the model acetabulum surface is currently being investigated.Many of the limitations discussed above concern the differences between the clinical setting and this model. Therefore, the exact values for the diametric shrinkage may not be accurate. This in vitro study was an attempt to simplify the complex process that occur in vivo during cemented acetabular cup implantation and reduce confounding factors so that there could be confidence in the conclusions drawn.It was previously known that PMMA bone cement shrinks during polymerisation, however, the magnitude of the shrinkage for vacuum and non-vacuum mixed cement mantles for cemented hip replacements was not known.This study found that the average size of the interstice created between the cement mantle and bone when a 50 mm diameter flanged acetabular cup is implanted into a 52 mm mock acetabulum is 0.39 mm ± 0.15 mm when the cement is mixed in non-vacuum conditions and 0.60 mm ± 0.09 mm when the cement is mixed under vacuum. This interstice is uniform across the cement mantle for each mixing methodology.34 It has been shown that immediate postoperative radiolucent lines are a good indicator for early failure of total hip arthroplasty.47 The cause of these lines has been thoroughly debated in the literature; the evidence presented here suggests that shrinkage of the bone cement is probably a contributing factor to these radiolucent lines and consequent early failure of cemented acetabular cups, especially when vacuum mixed. The cement mantle shrinkage may also provide a larger migration path for wear debris and increase the risk of periprosthetic osteolysis as a result.These findings offer an explanation for the increased risk of failure in the first 4 to 5 years after total hip arthroplasty when the cement is vacuum mixed compared to when it is mixed in non-vacuum conditions.Caution should be taken not to presume that the optimal cementing technique has been established. The best clinical evidence for determination of efficacy of operative techniques is arthroplasty registries, unfortunately many registries do not contain enough detail to make any conclusions regarding cement preparation techniques.


There are many glucose-lowering agents used in patients with heart failure, showing mixed results, this study was conducted to determine the effect of liraglutide, a glucagon-like peptide-1 analogue, on the treatment of patients with heart failure. Patients from the FIGHT and LIVE trials were included, all overlapped data were summarized and described. No significant changes from baseline in left ventricular ejection fraction, N-terminal pro-B-type natriuretic peptide, hemoglobin A1c, heart rate, left ventricular end-systolic volume index, left ventricular end-diastolic volume index, and 6 min walk test were observed in FIGHT. In LIVE, liraglutide significantly decreased hemoglobin A1c and inceased 6 min walk test and increased heart rate and serious cardiac adverse events, and there were no statistical differences in left ventricular ejection fraction, N-terminal pro-B-type natriuretic peptide, left ventricular end-systolic volume index, and left ventricular end-diastolic volume index. In this study, we found that there is not enough reason to support the use of liraglutide in patients with heart failure, and importantly, the safety of liraglutide in this particular population remains uncertain. Enhanced recognition the risks and benefits of liraglutide would help guide therapeutic decisions in patients with heart failure. Heart failure (HF) affects at least 26 million people worldwide, and the prevalence is increasing year by year. HF patients experience a high burden of symptoms and functional limitations, and morbidity and mortality remain high despite successful therapies . Type 2 We included all perticipants from the Functional Impact of GLP-1 for Heart Failure Treatmen (FIGHT)  and EffeP < 0.0001) and inceased 6 min walk test (P = 0.04) and heart rate (P < 0.0001), compared with placebo. There were no statistical differences in the influence of the abovementioned outcomes that coincided with FIGHT  among patients with T2DM and high cardiovascular risk was lower with liraglutide than with placebo, whereas the number of hospitaion for HF was reduced non-significantly in the active arm . The encIn this study, we found that there is not enough reason to support the use of liraglutide in patients with HF, which is consistent with the latest updated meta-analysis of 43 randomized controlled trials . AnotherIn summary, the results of the body of existing evidence do not support the use of liraglutide in HF. Importantly, the safety of liraglutide in this particular population remains uncertain. Therefore, further studies are needed to assess the risks and benefits of liraglutide in patients with HF.


We performed layer-specific strain analysis with speckle-tracking echocardiography to investigate the transmural difference of myocardial damage as the predicting factor for the viability of damaged myocardium in patients with ST segment elevation myocardial infarction (STEMI). We analysed patients with acute STEMI who had undergone primary percutaneous coronary intervention and echocardiography within 24 h from the intervention and 2 months after the event. Segmental strains of the left ventricular (LV) endocardium, myocardium, epicardium, and strain gradient (SG) between the endocardium and epicardium were evaluated. In 34 patients, 112 akinetic/dyskinetic and 94 hypokinetic segments were observed among 612 segments of the LV at baseline, and 65 akinetic/dyskinetic segments had viability. In our study, layer-specific strains were gradually deteriorated by their wall motion. SG was augmented in the hypokinetic segments where inhomogeneous wall motion impairment was progressed. SG in the akinetic/dyskinetic segments was different between the viable and non-viable myocardium and was maintained in viable segments. We therefore believe that significantly reduced SG is indicative of irreversible transmural damage in the acute stage of STEMI and can be suitably used as a parameter for predicting myocardial viability. Therefore, the viability of an akinetic or dyskinetic but stunned myocardium should be assessed for the long-term prognosis of patients with AMI5.After an acute myocardial infarction (AMI), a substantial part of the damaged myocardium recovers from the dysfunction6. Within 60 min, the inner third of the LV wall becomes irreversibly injured; and within 6 h, the transmural extent of infarction is observed in the absence of collateral flow. Therefore, the difference in myocardial function between the endocardium and the epicardium could be associated with the presence of coronary artery disease7 and is expected to reflect irreversible myocardial damage. Recently, speckle-tracking echocardiography has been acknowledged to evaluate myocardial systolic function more accurately than the conventional echocardiography8. A detailed layer-specific analysis of LV function is possible with strain analysis, which enables separate analysis of endocardial myocardial, and epicardial deformation. This method allows transmural evaluation of myocardial damage in patients with AMI10.The left ventricular (LV) myocardium is composed of three layers, and there are transmural inhomogeneity in a damaged myocardium with AMI. When a coronary artery occlusion develops, myocardial damage starts from the endocardium and progresses as a wave front to the epicardiumWe hypothesized that the difference in myocardial strain between the endocardium and epicardium  of the damaged segment could be indicative of the transmural extent of myocardial damage. Parameters such as SG and layer-specific segmental strain could be important prognostic factors to predict the viability of the akinetic or dyskinetic segment. Therefore, in this study, we performed layer-specific strain analysis with speckle-tracking echocardiography to investigate the association of strain parameters and the viability of damaged myocardium in patients with AMI.p = 0.02) and global longitudinal strain  significantly improved.A total of 34 patients with ST segment elevation myocardial infarction (STEMI) were enrolled in the study. The mean age was 60 ± 11 years, and 28 patients were men. Twenty-five patients had anterior wall myocardial infarction. Peak CK-MB level was 229.1 ± 128.6 μg/L. Their ejection fraction was 50.2 ± 9.9% and global longitudinal strain of left ventricle was -10.9 ± 4.3% at baseline  increased from the epicardial (LSepi) layer to the myocardial (LSmyo) and endocardial (LSepi) layers  and this trend was also observed in hypokinetic segments  and akinetic or dyskinetic segments .p < 0.001 for LSendo, LSmyo and LSepi). However, SG of the hypokinetic segment was significantly augmented in compare to SG of normokinetic segments ; there was no significant difference in SG between normokinetic segments and akinetic or dyskinetic segments (p = 1.00) . SG was also significantly greater in viable segments . In the follow-up study, segmental strains and SG of viable segments were significantly greater than those of non-viable segments  analysis to evaluate the predictability of viability with layer-specific segmental strains Fig. . Area unICCs for intraobserver and interobserver variability of LSendo were 0.96  and 0.910 , of LSmyo were 0.970  and 0.932 , of LSepi were 0.968 , and 0.940 , and of strain gradient were 0.834  and 0.708 . The intraobserver and interobserver variability was excellent for LSendo, LS myo and LSepi and good for strain gradient.To the best of our knowledge, this is the first study on the assessment of LV function with layer-specific strain analysis in patients with STEMI undergoing primary percutaneous coronary intervention. The main findings of this study are (i) segmental strains of damaged LV gradually deteriorated with their wall motion, both in the endocardium and epicardium, and LSs were significantly different in each layer in normokinetic, hypokinetic and akinetic or dyskinetic segments; (ii) SG was augmented in hypokinetic segments where inhomogeneous wall motion impairment was progressed; (iii) akinetic or dyskinetic but viable segments exhibited higher LSs in all three layers and SG than non-viable segments exhibited; (iv) SG was only different in akinetic or dyskinetic segments and showed the best predictability for segmental viability.11 because of its influence on LV function, symptoms of heart failure, and cardiovascular outcome when revascularization and medical therapy are properly performed14. Therefore, there have been several efforts to predict the viability of LV using non-invasive imaging modalities. Nuclear imaging15, ultrasonography17, and magnetic resonance imaging18 provided optimal values for predicting myocardial viability with good sensitivity and specificity. However, some of these modalities are very expensive, and require patients to be administered a radionuclide to enhance contrast for evaluation. Moreover, nuclear imaging and dobutamine stress echocardiography require stress to be given to the patient19, which may be inappropriate and harmful in acute stages of myocardial infarction20. Therefore, evaluation using such methods is not possible in patients with AMI. In this study, myocardial viability was evaluated using echocardiography without additional injection of contrast agents or stressors. Speckle-tracking analysis requires only a two-dimensional echocardiographic image of proper quality, which does not harm the patient, yet, provides additional information to the physician and patient21.Viability of damaged myocardium after myocardial infarction is an important prognostic factor22. Therefore, the evaluation of transmurality of myocardial damage and the degree of endocardial damage play an important role in the prognosis of coronary artery disease. Detection of myocardial damage limited to the endocardial layer without significant decrease in LV global function suggested the high probability of the presence of coronary artery disease in patients with chest pain23. In addition, the extension of myocardial damage to the epicardial layer suggested poor prognosis of ischemic heart disease leading to irreversible myocardial damage24. Likewise, an independent analysis of endocardial and epicardial strain and the evaluation of the difference between them are expected to discriminate the transmurality of myocardial damage in coronary artery disease. In this study, a gradual decrease of segmental strains was observed in the myocardium with deterioration of wall motion from normokinesia to hypokinesia and akinesia or dyskinesia. However, SG was rather increased in hypokinetic segment where wall motion was inhomogeneously impaired; it was not changed in the akinetic segments. This suggests that transmurality of the wall motion impairment only influenced the SG. SG was significantly decreased only in non-viable myocardium even in the akinetic or dyskinetic segments.Myocardial injury due to ischemic heart disease starts from the endocardium, and spreads to the myocardium and epicardium due to the epicardial location of the coronary arteries and LV systolic pressure gradient during systole, which is called the wave front phenomenon25. In our study, change in ejection fraction between the baseline and follow-up studies was approximately 4.08 ± 7.93%, change in GLS was 4.29 ± 8.47%, and the changes in segmental strain values of damaged myocardium were much greater. Therefore, we expect that risk assessment for viability with segmental strain parameters provides detailed information with no additional image acquisition or hazard to the patients in clinical practice.Evaluation of the global function using parameters such as ejection fraction or global longitudinal strain yield very small changes in these values because they incorporate both damaged and undamaged myocardium. Therefore, the evaluation of regional myocardial function has been reported to have superior prognostic implications in patients with acute myocardial infarctionThe total number of patients in this study was small. However, the primary outcome of the study was segmental viability, which was evaluated in 112 akinetic or dyskinetic segments using linear mixed model. And, the statistical power of the analysis was enough to evaluate the influence of viability on segmental strain values and strain gradient especially in LSendo and SG; > 0.955 and 0.985 for each. Even in a patient with severely damaged left ventricle, the undamaged segments have normal segmental strain values whereas the damaged segments have worse result. Therefore, our evaluation may not be appropriate for the direct clinical prognosis prediction. Although we could not predict the risk of major adverse cardiac events with this evaluation, we thoroughly evaluated the viability of damaged segments after acute STEMI. We excluded patients who exhibited cardiac arrhythmia including atrial fibrillation for more accurate analysis of layer-specific strain and patients who did not have a follow-up image including those who died before the follow-up study. This implies that we may have excluded patients with more severe disease.Layer-specific segmental strain and SG were significantly different between normokinetic segments and akinetic or dyskinetic segments. Transmural difference represented by SG was increased in the hypokinetic segments where inhomogeneous wall motion impairment was progressed, but was maintained in the akinetic or dyskinetic segments. SG in the akinetic or dyskinetic segments was significantly reduced in non-viable segments and showed significant predictability for segmental viability. Therefore, SG in the acute stage of STEMI can be suitably used as a parameter for predicting myocardial viability.Patients who visited the emergency department due to chest pain and diagnosed with STEMI were screened. If chest pain started within 24 h of the visit to the emergency room and primary percutaneous coronary intervention was performed, the patients were enrolled for the study. Patients with a history of coronary artery disease, structural heart disease, or cardiac arrhythmia, who did not undergo follow-up imaging, and did not give informed consent were excluded. This study was approved by Institutional Review Board of Korea University Anam Hospital, Seoul, South Korea and performed in accordance with relevant guidelines and regulations in accordance with the Declaration of Helsinki.26. LV hypertrophy was defined as LV mass index of > 95 g/m2 in women and > 115 g/m2 in men. LV ejection fraction was calculated using the modified Simpson’s method from apical four- and two-chamber views, and the LV volume was measured at the ventricular end systole and end diastole. Mitral inflow was obtained using pulse-wave Doppler echocardiography with the sample volume between mitral leaflet tips during diastole. Myocardial movement was categorized into three grades: normokinesia, hypokinesia and akinesia or dyskinesia. Viability was analysed in terms of the improvement in segmental movement of akinetic or dyskinetic segment by more than a grade during the follow-up study; for example, akinesia or dyskinesia to hypokinesia or normokinesia.Both conventional two-dimensional echocardiography and speckle-tracking echocardiography were performed at baseline and follow-up. Baseline evaluation was performed within 24 h of revascularization, and follow-up echocardiography was performed 6–10 weeks after revascularization. All echocardiographic measurements were performed using a commercially available ultrasound system . Chamber diameter and wall thickness were measured directly from two-dimensional echocardiographic images, and LV mass was evaluated by linear measurements using the formula recommended by the European Association of Cardiovascular ImagingTo evaluate the layer-specific strain, apical four-chamber, two-chamber, and long-axis views were recorded with a frame rate of 60–80 frame/s during baseline and follow-up echocardiographic evaluations. Then, strain analysis was performed with the off-line software . After manual tracing of the endocardial border of the LV in three apical images, endocardial, myocardial, and epicardial segmental and global LSs were obtained using LSendo, LSmyo, and LSepi, respectively, for segmental layer-specific LS. Segmental SG between the endocardium and epicardium was also calculated according to the difference in LSendo and LSepi in each segment. For the analysis of segmental viability, we checked the correlation between the culprit coronary artery and the region of the akinetic or dyskinetic segment.Continuous variables were expressed as mean ± standard deviation, and categorical variables as frequencies and percentages. Segmental strain parameters between layers and between baseline and follow-up studies were compared using repeated measure ANOVA. The influence of wall motion and viability on segmental strain parameters were evaluated using linear mixed model. We performed receiver operating characteristic curve analysis to evaluate the predictability of the viability using layer-specific segmental strains and SG. To assess the reproducibility of the variables, LSendo, LSmyo, LSepi and strain gradient were repeatedly evaluated on the same echocardiographic images of ten patients. Then, we assessed the intra-observer variability and inter-observer variability using intraclass correlation coefficient (ICC). All statistical analysis was performed with SPSS version 20.0  and SAS version 9.4 .


In patients with advanced liver disease, portal hypertension is an important risk factor, leading to complications such as esophageal variceal bleeding, ascites, and hepatic encephalopathy. This study aimed to determine the diagnostic value of T1 and T2 mapping and extracellular volume fraction (ECV) for the non-invasive assessment of portal hypertension.In this prospective study, 50 participants (33 patients with indication for trans-jugular intrahepatic portosystemic shunt (TIPS) and 17 healthy volunteers) underwent MRI. The derivation and validation cohorts included 40 and 10 participants, respectively. T1 and T2 relaxation times and ECV of the liver and the spleen were assessed using quantitative mapping techniques. Direct hepatic venous pressure gradient (HVPG) and portal pressure measurements were performed during TIPS procedure. ROC analysis was performed to compare diagnostic performance.r = 0.72; p < 0.001) and direct HVPG . No significant correlations were found between native splenic T1 and T2 relaxation times with portal pressure measurements . In the derivation cohort, splenic ECV revealed a perfect diagnostic performance with an AUC of 1.000 for the identification of clinically significant portal hypertension (direct HVPG ≥ 10 mmHg) and outperformed other parameters: hepatic T2 , splenic T2 , and splenic native T1  . The diagnostic performance of mapping parameters was comparable in the validation cohort.Splenic ECV correlated with portal pressure (Splenic ECV was associated with portal pressure measurements in patients with advanced liver disease. Future studies should explore the diagnostic value of parametric mapping accross a broader range of pressure values.• Non-invasive assessment and monitoring of portal hypertension is an area of unmet interest.• Splenic extracellular volume fraction is strongly associated with portal pressure in patients with end-stage liver disease.Quantitative splenic and hepatic MRI-derived parameters have a potential to become a new non-invasive diagnostic parameter to assess and monitor portal pressure.•  Any chronic liver disease may lead to liver fibrosis, which distorts normal liver architecture by the expansion of the extracellular space, and impairs hepatic function . Liver cRecently, quantitative T1 and T2 mapping techniques have been applied to the liver and spleen and might be used for tissue characterization and for the staging of liver fibrosis , 8. FurtThis prospective, proof-of-concept study was approved by the institutional review committee. All study participants provided written informed consent prior to MRI examination. From November 2018 to September 2019, patients with advanced liver disease and portal hypertension scheduled for trans-jugular intrahepatic portosystemic shunt (TIPS) implantation were consecutively included in this study. All patients completed MRI before TIPS implantation. Healthy volunteers underwent MRI as controls. Diagnosis of refractory ascites was based on the diagnostic criteria recommended by the International Ascites Club (IAC) . ClinicaAll imaging was performed on a clinical whole-body 1.5-T MRI system  equipped with 32-channel abdominal coil with digital interface for signal reception. Besides morphological sequences, patients underwent parametric mapping MRI of the liver and the spleen: For splenic and hepatic T1 mapping, a heart rate independent10-(2)-7-(2)-5-(2)-3-(2) modified Look-Locker inversion recovery (MOLLI) acquisition scheme  with intTIPS procedures establish an artificial connection between the portal and systemic circulation. It is applied in patients with end-stage liver disease for reduction of the portal pressure . TIPS pr2. The ROIs were firstly placed into the native T1 map. Afterward, the ROIs were copied on all other relaxation maps for the same patient. Mean T1 and T2 relaxation times were used for analysis. T1 values of the blood pool were obtained from the abdominal aorta. ECV values were normalized for hematocrit and calculated from pre- and post-contrast T1 values using the following equation [Image analyses were performed by an experienced board-certified radiologist, blinded to the clinical information and portal vein pressure measurements. Three regions of interest (ROIs) were respectively drawn within the liver and the spleen parenchyma, away from confounding factors like vessels, biliary structures, and organ boundaries. Minimum ROI size was ≥ 1 cmequation : ECV = (equation . Blood ht test. Dichotomous variables were compared by using the χ2 test. Pearson correlation coefficient (r) was used for correlation analyses. In the derivation cohort, the diagnostic performance of MRI parameters was analyzed by plotting receiver operating characteristics and comparing the area under the curve (AUC). Youden’s index was used to determine the optimal cutoff of the ROC curve providing the highest combination of sensitivity and specificity. The presence of clinically significant portal hypertension (direct HVPG ≥ 10 mmHg) was the reference standard against which the diagnostic performance of MRI-derived mapping parameters of spleen and liver was tested. AUCs were compared by using the method proposed by DeLong et al [p < 0.05.Statistical analysis was performed using SPSS Statistics  and MedCalc . Patient characteristics are presented as mean ± standard deviation or as absolute frequency. Continuous variables between the two groups were compared by using the Student A total of 33 patients with liver cirrhosis and refractory ascites/esophageal variceal bleeding and 17 healthy volunteers were included. The first 40 participants  were used as a derivation cohort to establish the cutoff values of mapping parameters. The next 10 participants that were included constituted our validation cohort . The mean interval between pre-interventional MRI and TIPS implantation was 9.66 ± 11.87 days. All patients had clinically significant portal hypertension (direct HVPG ≥ 10 mmHg). There were no peri- or post-procedural complications related to TIPS implantation.n = 14, 50.00%), non-alcoholic fatty liver disease , virus-related liver cirrhosis , toxic liver disease , unknown etiology , and sinusoidal liver disease . Indications for TIPS implantation were refractory ascites  and esophageal variceal bleeding .Etiologies of liver disease included alcoholic liver disease  and unknown etiology . Indications for TIPS implantation were refractory ascites  and esophageal variceal bleeding . The clinical characteristics of the derivation and validation cohorts are summarized in Table Etiologies of liver disease included alcoholic liver disease  and direct HVPG  were significantly correlated with splenic ECV in cirrhotic patients , T2 relaxation times , and splenic ECV values . There were significant differences in hepatic MRI parameters between controls and patients: native T1 relaxation time  and ECV . No significant differences in hepatic T2 relaxation times were present between both groups .Compared with healthy controls, patients with liver cirrhosis had significant increased splenic native T1 relaxation times . The diagnostic performance of splenic ECV was also not significantly higher compared with that of hepatic native T1  but significantly higher than that of splenic native T1 . There were no significant differences in the diagnostic performance of native splenic and hepatic T1 . Hepatic ECV showed a higher diagnostic performance compared with native splenic T1 . Between hepatic ECV and hepatic native T1, no significant differences in diagnostic performance were observed. The diagnostic performance of hepatic and splenic T2 was significantly lower than that of the splenic and hepatic native T1 and ECV parameters.Splenic ECV revealed a perfect diagnostic performance with an area under the curve (AUC) of 1.000, a sensitivity of 100%, and a specificity of 100% see Fig. . There wThe parameters of the diagnostic performance of the validation cohort are given in Table In our proof-of-principle study, we evaluated different parametric MRI parameters for non-invasive assessment of portal hypertension. The main findings of our study are that (1) splenic ECV showed a statistically significant correlation with portal pressure and direct HVPG and, (2) splenic and hepatic ECV showed a high diagnostic performance to diagnose clinically significant portal hypertension and performed better than native T1 and T2 mapping parameters.Hepatocyte injury in chronic liver disease leads can activate potentially fibrogenic cells and promote the occurrence of liver fibrosis. The formation of liver fibrosis leads to an increased deposition of abnormal extracellular matrix components . Liver fPortal hypertension initially develops because of increased intrahepatic resistance to the passage of blood flow through the liver as a consequence of hepatic fibrotic changes. In this regard, splenomegaly in liver disease is likely to be a consequence of portal congestion with blood pooling as well as pulp hyperplasia and fibrosis . All theTo our knowledge, there are still no studies directly showing correlations between invasive measured direct HVPG in patients with end-stage liver disease and clinically significant portal hypertension and splenic ECV as a non-invasive marker of portal pressure. Splenic ECV showed a perfect diagnostic performance for clinically significant portal hypertension with an AUC of 1.000 in the derivation cohort. Moreover, although not statistically significant, the diagnostic performance of splenic ECV was superior to that of the liver, possibly because liver fibrosis reflects only one element of pathophysiological changes in portal hypertension, while splenic ECV directly reflects all consequences of portal hypertension . ECV measurements also showed a higher diagnostic performance compared with T1 and T2 mapping parameters, probably because ECV is a physiologically normalized measure and reflects changes of splenic parenchyma more accurately. Therefore, ECV seems to be a stable and biologically significant biomarker for non-invasive assessment of portal hypertension.r = 0.69, p = 0.001), we did not found significant correlations between the post-contrast splenic T1 and direct HVPG measures. This might be explained due to our very homogeneous patient collective with end-stage liver disease and clinically significant portal hypertension (mean direct HVPG 20.71 ± 5.49 mmHg). In the previous study, only half of the patients (47%) had clinically significant portal hypertension [Splenic post-contrast T1 has also been recognized as a potential biomarker for diagnosing portal hypertension as well as for treatment monitoring and prognosis . In contrtension , which mUnlike ECV, native hepatic T1 (AUC 0.926) performed better than native splenic T1 (AUC 0.806) in the derivation cohort. This might be explained by a higher contribution of fibrosis to changes in T1 values, as fibrotic changes are more remarkable in hepatic than in splenic parenchyma. Splenic and hepatic T2 mapping parameters had a similar diagnostic performance to patients diagnosed with clinically significant portal hypertension with AUCs of 0.736 and 0.731, respectively. According to previous cardiac studies, increased T2 relaxation times are mainly driven due to myocardial edema or inflammation . TherefoHowever, hepatic and splenic mapping is a rapidly evolving field and standardized protocols are still being established. Unlike CT, MRI techniques have the advantages that they do not require radiation dose for the assessment of portal hypertension . Also, iDespite the advantages of ECV measurements as a potential non-invasive parameter, our study has several limitations. First, only patients with end-stage liver disease and significant portal hypertension were included in our explorative study. Therefore, only a small homogenous population with HVPG ≥ 10 mmHg was observed and no conclusion about a broader range of portal pressure measurement can be drawn. As direct portal pressure measurements in patients without indication for TIPS procedure are not clinical routine in our clinic, diagnostic performance of mapping parameters was tested against a control group and not against a patient group without a significant portal hypertension. Therefore, the selected study design does not represent a real-life setting and reported parameters of diagnostic performance have to be regarded as study specific. T1 and T2 maps were acquired in a single transverse section at the level of the bifurcation of portal vein and, therefore, may have missed other significant changes, which probably occurred in other planes. Furthermore, our T1 measurements were not corrected for hepatic steatosis or hepatic/splenic iron overload, which might impair the correct assessment of T1 values , 30. AnoIn conclusion, in our prospective proof-of-principle study, quantitative splenic and hepatic MRI-derived parameters including ECV appear to be a new valuable, non-invasive diagnostic parameter for the assessment of portal pressure in patients with advanced liver disease. Especially, splenic ECV might provide important information about the presence of clinically significant portal hypertension.


We present a unique case study report of a male individual with a history of mild nonischaemic cardiomyopathy, with no ventricular ectopy, that at the age of 76 years sustained multiple concussions  within a week of each other. Concussion symptoms included cognitive difficulties, “not feeling well,” lethargy, fatigue, and signs of depression. He was later medically diagnosed with postconcussion syndrome. The patient, WJT, was referred for cardiac and neurological assessment. Structural neuroimaging of the brain (MRI) was unremarkable, but electrocardiography (ECG) assessments using a 24-hour Holter monitor revealed significant incidence of ventricular ectopy  over a period of 5–6 months after injury and then a further increase in ventricular ectopy to 18%  during the subsequent 3 months. The patient was then prescribed Amiodarone 200 mg, and his ventricular ectopy and concussion symptoms completely resolved simultaneously within days. To the authors' knowledge, our study is the first to show a direct link between observable and documented cardiac dysregulation and concussion symptomology. Our study has important implications for both cardiac patients and the patients that sustain a concussion, and if medically managed with appropriate pharmacological intervention, it can reverse ventricular ectopy and concussion symptomology. More research is warranted to investigate the mechanisms for this dramatic and remarkable change in cardiac and cerebral functions and to further explore the brain-heart interaction and the intricate autonomic interaction that exists between the extrinsic and intracardiac nervous systems. There is a significant body of literature to show that neuroautonomic cardiovascular dysregulation can occur as a result of a concussion or mild traumatic brain injury (mTBI). Much of this research has used heart rate variability, blood pressure variability, cerebral blood flow metrics, and baroreflex sensitivity to try to diagnose the extent of autonomic nervous system (ANS) dysregulation –12. MechFurthermore, there is an accumulation of research that has investigated the brain-heart (heart-brain) relationship and interaction, specifically an advancing field of study called “neurocardiology” and the neurocardiac axis theory –21. NeurThe stuctural and functional organization of cardiac innervation in the neurocardiac axis is illustrated by Shivkumar et al . Their iThus, the purpose of this case study was to report two novel findings as follows: (1) mTBI caused cardiac arrhythmias, which is consistent with the theory of a neurocardiac axis and (2) pharmacological intervention with Amiodarone administration completely reversed cardiac dysregulation and concussion symptomology simultaneously within days.th December 1997 (age 57 yrs) to show that he had minor symptoms of ventricular ectopy, left bundle branch block (LBBB), and mild nonischaemic cardiomyopathy. When assessed almost 8 years later (6th July 2005), his cardiovascular examination was not significantly changed and was normal with no carotid bruits, normal jugular venous pressure, normal heart sounds with no murmurs, and clear lung fields. He was not taking any medications . His ECG demonstrated a normal sinus rhythm with a LBBB. No ectopy was seen. However, a dipyridamole sestamibi myocardial nuclear perfusion scan was ordered because the patient experienced an increased frequency of atypical chest discomfort during the previous couple of months. The scan was abnormal, documenting an ejection fraction (EF) of 39% with a dilated left ventricle and a left ventricular end-diastolic volume (LVEDV) of 171 mL. There was a mild reduction in tracer uptake in the septum, which was consistent with the LBBB artefact. No definite ischaemia was identified. The patient was started on Inhibace 0.5 mg. The goal was ultimately to increase his angiotensin-converting enzyme (ACE) inhibitor to a maximal dose and reconsider the role of a β-blocker [The earliest medical files on patient WJT on record is dated 4-blocker .His follow-up assessment in October 2005 included an angiogram that showed minimal coronary disease and surprisingly normal LV function with an EF of 73% and normal left ventricular volume when assessed using LV ventriculography , 28. The2; EF 70%). Blood pressure (varied from 138/85 to 145/95 mmHg) and cholesterol profile  remained relatively healthy (now age 73 yrs).Regular follow-ups continued every 6–12 months from 2005 to 2013 that included ECG, echocardiography, chest examinations, and prescription drug management as per normal medical practice in an ageing patient with some history of cardiovascular disease. During this period, WJT was generally well and unlimited in terms of his activities of daily living, including hiking, skiing, and hunting. He was maintained on various medications to ensure an active healthy lifestyle and to control for his history of mild nonischaemic cardiomyopathy. Medications over this period of time included Inhibace 2.5 mg, short-acting Diltiazem 30 mg, Metoprolol 50 mg, angiotensin receptor blocker, Aspirin, Atacand (Candesartan) 8 mg, and Diazepam 2 mg, and his Candesartan 8 mg was switched at that stage to Losartan 25 mg. Cardiac structure and function remained typically the same with normal systolic and diastolic function, interatrial septum intact, EF%, and no valvular disease (left ventricular end-diastolic diameter (LVEDD) = 5.8 cm, end-systolic diameter (ESD) = 3.9 cm, interventricular septum (IVS) = 1.1 cm, left ventricular posterior wall thickness (LVPW) = 0.9 cm; left atrium measures 20 cmIn November 2013, patient WJT had a 24-hour Holter that revealed only a very minimal amount of ectopy  althoughth September and the second on 6th October 2016. These were later medically diagnosed as a concussion or mTBI. Because of his symptoms of increased ectopy and change in perception of cognitive function, WJT contacted us with concerns about his increased ectopy and malaise. WJT reported that these symptoms had been progressing over the past 5-6 months since his concussions. Symptoms included cognitive “deterioration,” “not feeling well,” headache, “lack of energy and fatigue,” “irritability,” signs of depression, and “acute audio sensitivity and poor visual acuity” which were the two most extreme, persistent and troubling symptoms that WJT experienced.The patient WJT was 76 years old when he sustained two concussions within approximately 10 days: the first on 26th March 2017, he undertook a 24-hour Holter monitor which showed a high burden of ventricular ectopy at 9.4% . This is in stark contrast to his 24-hour Holter in 2013 where there were negligible ectopic beats , he performed another resting echocardiogram and exercise stress echocardiogram. Resting echocardiogram revealed that the left ventricle was normal in size and had low-normal systolic function with an estimated EF of 50%. There was considerable beat-to-beat variability depending on the degree of ectopy. Measurements included LVEDD = 5.1 cm; ESD = 3.1 cm; IVS = 1.1 cm; LVPW = 1.1 cm; and EF 50%. The patient completed 8 minutes of the Bruce protocol achieving 95% maximal predicted heart rate with blood pressure rising from rest at 138/70 to 182/85 mmHg at the termination of exercise. Again, adverse cardiac symptoms did not limit this test. WJT felt well throughout the stress test, and the resting monomorphic ventricular ectopy was resolved at peak stress. The ECG showed LBBB throughout the assessment. The impression of the stress echocardiogram at peak exercise suggested that there was an acceptable augmentation of wall thickening in all myocardial segments without clear evidence for ischaemia. Image quality was good. Thus, the exercise stress echocardiograph demonstrated a mild nonischaemic cardiomyopathy as previously known without significant ischaemia at stress and no significant change from 2013.Although his May–June 2017 echocardiographic assessments and follow-up showed only minor changes from November 2013, the high percentage of ventricular ectopy (9.4%) was problematic for the patient. He stated that he had periods of depression. He did not feel right and expressed concerns about his cognition; again, this was likely a result of his two back-to-back concussions. Based on his description of symptoms that he was experiencing, it is likely that he had been suffering from postconcussion syndrome , 31. Theth July 2017) showed another significant increase in ventricular ectopy at 18.1%  confirmed an absence of ventricular ectopy . The resolution of the ventricular ectopy was successfully managed with Amiodarone, as was his postconcussion symptoms. He remained stabilised on the 200 mg dose of Amiodarone.His follow-up 24-hour Holter monitor (25rd May 2018). At this time, the patient was stopped from taking Amiodarone completely and prescribed his longstanding Losartan 25 mg. His follow-up 24h-hour Holter monitor on 16th October 2018 showed that ventricular ectopy was 0.2% . At this time, no further postconcussion symptoms were reported.Because of the concern regarding the long-term side effects of Amiodarone, his dosage was dropped 100 mg and kept for 3 months and then dropped again to 50 mg thereafter (February 2018). WJT felt completely well on the 50 mg dose of Amiodarone for a good period of time (March to June 2018). Despite the substantial dose reduction, he remained free of any important ventricular ectopy with a very low burden of ventricular dysrhythmia  on his most recent 24-hour Holter monitor .This was a retrospective study that was approved by a University Research Ethics Board (REB #2018-113), and all work was conducted in accordance with the Declaration of Helsinki (1964). The patient WJT provided his written informed consent to have all of his medical records available for this case study report. Patient WJT DOB is 23th November 2013). However, the HRV software was consistent for all recording dates after the concussions. Fast Fourier transformation using Welch's periodgram method for frequency-domain and time-domain spectral analyses was used to determine HRV metrics [The data were acquired from all medical records from 1997 to 2018 and put into Microsoft Excel spreadsheet  for ease of data management and interpretation. The ventricular and supraventricular  data were taken from the 24-hour Holter monitor . Heart rate variability (HRV) data were taken from the printed Holter monitor report. We attempted to get the raw ECG data to conduct our own HRV analysis, but this was not possible due to restrictions of the manufacturer. HRV was not conducted during the preconcussion 24-hour Holter monitoring (4 metrics .The results for this case study report are presented in Tables th March 2017 (9.4% ventricular ectopy) and 6th July 2017 (18% ventricular ectopy). Furthermore, this increase in the LF : HF ratio with an increase in ventricular ectopy does suggest a potential impairment in the sympathovagal balance of HRV [th March 2017 to 21st February 2018.The nonlinear analysis of the ECG has been used to derive HRV , by anale of HRV . Howevere of HRV . All othThis is the first study, to our knowledge, to show direct evidence that acute mTBI and subsequent postconcussion syndrome symptomology can cause cardiac arrhythmias and that the symptoms of mTBI and ventricular dysregulation were completely abolished within days with pharmacological intervention of Amiodarone in our patient. This is a novel finding.It has been proposed in the brain-heart link, that there are intracardiac sensory neurons that relay sensory information back to the brain via the dorsal root and nodose ganglion , 19, 41.+2 channels and mitochondrial function [The precise mechanism(s) for the surprisingly high increased ventricular ectopy 18.1%) in patient WJT stemming from his mild head injury is not completely known, but it has been proposed that higher brain centres or brain stem regions may participate in the arrhythmogenesis , 21. As .1% in pafunction –47. Thisfunction  that pro+2 and sodium channels and act as a α- and β-blocker [The precise physiological mechanism(s) for the remarkable reversal in ventricular ectopy and mTBI symptomology in our patient is not completely elucidated from our study data, but our results showed that pharmacological intervention with Amiodarone reestablished the cardiac intracellular milieu and autonomic function. Amiodarone is a class III antiarrhythmic agent, is a multichannel blocker that has been shown to block potassium rectifier currents responsible for cardiac repolarization , and has-blocker –52. Thus-blocker .In addition to working directly on cardiac tissue to reverse the ventricular arrhythmia, Amiodarone has been shown to alter cerebral chemical channels too . Using aIn this study, we also used HRV as a surrogate measure to assess autonomic nervous system function , 54–56. Concomitant with the administration of Amiodarone for our patient WJT, these results showed that with the remarkable reduction of ventricular ectopy, there was also a concomitant reduction of LF : HF ratio . This inIn conclusion, this case study research suggests that concussion or mTBI can cause physiologic manifestations to cardiac tissue directly and support the literature showing a direct link between the heart and the brain during pathology. The mechanism for the reported cardiac dysregulation in our patient was likely related to ANS dysfunction. Our novel finding is that when we treated the heart with Amiodarone, all concussion symptoms and ventricular ectopy disappeared completely within days, further documenting the intricate relationship between the brain and the heart. Finally, the neurocardiac axis theory and neurogenic stunned myocardium phenomenon, both described above in the Introduction, could partly explain the brain-heart link and interaction and can thus pave the way to a better understanding and management of mTBI .