Along the years, the analysis of soccer referees perfomance has interested the experts and we can find several types of studies in literature using in particular cardiac imaging. The aim of this retrospective study was to observe relationship between VO2max uptake and some conventional and not-conventional echocardiographic parameters. In order to perform this evaluation, we have enrolled 20 referees, belonging to Italian Soccer Referees' Association and we have investigated cardiovascular profile of them. We found a strong direct relationship between VO2max and global longitudinal strain of left ventricle assessed by means of speckle tracking echocardiographic analysis (R2=0.8464). The most common classic echocardiographic indexes have showed mild relations . Therefore, our study suggests that longitudinal strain could be proposed as a specific echocardiographic parameter to evaluate the soccer referees performance. In literature, in the last two decades, we can find an increasing number of articles about soccer refereeing , 2. Castet al.  extensivet al. .In the last few years, some papers focused the attention on perceptual-cognitive expertise . HoweverRefereeing is substantially an endurance sport and therefore, along the last years there was a continuous evaluation of novel and/or efficient parameters to assay referees' performance. Knowledge of heart physiology and cardiovascular (CV) system is fundamental to investigate fitness performance and to select the most indicated tools as well as echocardiography that is increasing in importance , 9. Manyet al. soccer referees run on average about 12 km during each match [Generally, prolonged and intensive exercise modifies heart by increasing of mass, wall thickness and diameters of chambers. These changes of LV may differ in relation to the type of sport, body size, sex and race. Refereeing is properly long-time, continuous and intensive activity during a period of about 20-30 years; echocardiography is also pivotal for preventing hypertrophic heart diseases . MoreoveNowhere, in addition to classic panel of echocardiographic measurements we may use some novel techniques such as speckle tracking echocardiograhy (STE) which gives us a further instrument in left ventricle (LV) study , 14. MorFinally, the aims of our present study were to define the characteristics of LV myocardial mechanics as assessed by 2D STE in a group of top level referees and to correlate those findings with a traditional marker of aerobic power such as VO2max.We have consecutively studied 20 soccer referees, belonging to Italian Referees' Association. All of them were males aged 27 to 43 (mean 33.87±9.56). No one had hystory of heart disease.The subjects underwent a physical examination, a routinary 12-leads electrocardiography (ECG), an echocardiographic exam and a VO2max assessment by means of cardio-pulmonary exercise testing (CPET).All athletes agreed to take part in the study and provided written informed consent; the study protocol was approved by the institutional review board.Echocardiographic examinations were performed by expert cardiologists with specific competence in the evaluation of athletes, using a commercial ultrasound machine  equipped with an S5 probe (1-4 Mhz). 2D measurement of LV cavity diameters, wall thickness, mass were assessed according to American Society Echocardiography criteria .LV EF were measured with the biplane Simpson's rule from the apical four- and two-chambers views, while LV mass was measured with Devereux's formula . The DopAnalysis of 2D strain imaging was performed offline with commercially available software . This latest version was developed following the recommendation of a joint American Society of Echocardiography and American Heart Association document, aimed to improve standardization of the strain analysis and reduce intervendor variability .Apical four-chamber views were acquired achieving an high frame rate (70-80 frames/sec) and fitting the entire LV in the echocardiographic plane .Attention was paid to acquire cardiac cycles of the same standardized length and during the same respiratory phase (expiration); so, three cardiac cycles were stored in cine-loop format for off-line analysis in order to assess end-systolic LV longitudinal strain. The endocardial border was traced on an end-diastolic frame and subsequently automatically tracked; the tracking was verified in real time and corrected by adjusting the region of interest or manually correcting the border. End-systole was identified as corresponding to aortic valve closure as measured by pulsed-Doppler.The software represents myocardial deformation in the form of time-strain graphs in which it is possible to identify the different phases of the cardiac cycle as follows: a negative wave is observed during systole, which reaches its negative peak at the time of aortic valve closure and represents maximal longitudinal myocardial shortening during contraction; during diastole, the strain values progressively increase towards the original length.The time-strain curves were obtained and analysed by two independent observers who were blinded to the clinical data. Inter-observer variability was calculated using the Bland-Altman method to compare the measurements made by the two observers in 10 randomly selected subjects , and wasAll the referees enrolled were submitted to a treadmill CPET. Expired gases were analyzed using a commercial gas analyzer  that enabled VO2max data collection. Gas and HR sampling were performed in continuous as established by EACPR/AHA Position Paper .Data were expressed as mean ± standard deviation (SD). Relations with variables of interest were detected using simple linear regression (r).In a second phase, a Kruskal-Wallis ANOVA one way test was performed to assess how and which variables may better affect VO2max.p≤0.05).Significance was set for the calculations at 5%  and EF (p=0.03) showed a weak relation with VO2max. Total number of training sessions/year were not similarly related to VO2max.et al. it is tipical to discover athlete's heart with a normal EF in which hypertrophy is growing and modifying longitudinal deformation capability [Moreover, as already demonstrated by Urbano-Moral pability .Then, the best marker related to adjustments exercise-induced seem to be GLS and in fact, the best relation observed for VOmax was with GLS assessed with STE (p=0.002).Therefore, this innovative technique provides clinical and functional data which can efficiently differentiate physiological status and pathological one. For several years, we used only conventional echocardiography to measure exercise effects on cardiac morphology/function and diameters, volumes, EF and LV mass but the technology was not able to detect early functional adaptations of athletes' heart. Today, instead, we recommend to systematically apply STE and its derived indexes that are recognized to be important in the characterisation of myocardial properties and/or in distinguishing “athletes' heart” and cardiomyopathies.We know that all tracking techniques are more robust and reproducible for global rather than regional assessments. Moreover, GLS averaged from the apical views is the most important and reproducible of all LV deformation parameters and has been shown to be a powerful diagnostic and prognostic tool. This last consideration was also recently confirmed by recommendations for cardiac chambers quantification .However, literature has not totally clarified which determinants might potentially influence LV strain and so, GLS. In fact, it is still controversial if and how demographic features (including gender), haemodynamic factors and cardiac dimensions could affect GLS , 38.et al. [Different type of sports might also influence strain parameters as investigated by Caselli et al. .In any case, although the clear identification of items affecting LV strain measurements is still debated our findings confirm the emerging and promising role of STE for LV mechanics investigation in endurance athletes.In conclusion, this study confirmed the importance of imaging, especially echocardiography, for the assessment of athletes' heart performance in endurance athletes, as soccer referees, and seems to suggest STE as the echocardiographic tool most able to detect early modifications in LV mechanics before of conventional transthoracic echocardiography parameters. The main explanation could be identified in specific modality of STE which is a technique very very close to Torrent-Guasp model describing LV mechanics , 41.Finally, STE should become one of the most important approaches for studying sports' men, including soccer referees, and monitoring physical performance and possible induced pathophysiological mechanisms underlying sport activity along and for several years.


Arterial stiffness increases pressure load to the left ventricle (LV), leading to LV hypertrophy and subendocardial ischemia. Neurohormones stimulate myocardial fibrosis and LV dysfunction. We aimed to explore the associations of arterial stiffness and plasma aldosterone with multi-directional, layer-specific LV, and left atrial (LA) mechanical function in hypertensive patients.Layer-specific LV global longitudinal strain , global circumferential strain , LV torsional parameters, and LA global longitudinal strain (LA GLS) were analyzed by two-dimensional speckle tracking echocardiography in 195 hypertensive patients . Pulse wave velocity (PWV) was analyzed as a measure of arterial stiffness, and plasma aldosterone was measured for evaluation of neurohormonal activation.p = 0.031) and LA GLS  were independently correlated with PWV even after controlling for confounding factors.In a simple correlation, PWV significantly correlated with LV GLS-endo and LA GLS. Log aldosterone correlated with both LV GCS-endo and LV GCS-trans. Multiple regression analysis revealed that LV GLS-endo (β = 0.223, In hypertensive patients without clinically apparent target organ damage, LV GLS, especially endocardium, and LA GLS were more dominantly affected by arterial stiffness because, among the three myocardial layers, the endocardium is most susceptible to pressure overload. Two-dimensional layer-specific speckle-tracking echocardiography sensitively detects LV mechanical dysfunction and provides pathophysiologic insights into LV mechanical adaptations in hypertension. Cardiac remodeling in hypertensive disease is a complex process involving both mechanical stress from central arterial stiffness and neurohormonal factors . ArteriaProgressive remodeling of LV is suggested to be heterogeneous across the LV wall . The myoThe aim of this study was to explore the associations of central arterial stiffness and plasma aldosterone with layer-specific LV and LA mechanical function in patients with early hypertension using two-dimensional speckle tracking echocardiography.This study was designed as a retrospective cohort study. We included consecutive adult hypertensive patients without apparent end organ damage who underwent clinically indicated echocardiography between 2010 and 2015. Patients with reduced ejection fraction (< 50%), significant valvular heart disease, ischemic heart disease, idiopathic dilated cardiomyopathy, restrictive cardiomyopathy or hypertrophic cardiomyopathy, or atrial fibrillation were excluded from the study. Finally, a total of 195 patients were reviewed. Hypertension (HTN) was defined as systolic blood pressure (SBP) ≥ 140 mmHg, diastolic blood pressure (DBP) ≥ 90 mmHg, or current pharmacological treatment for HTN. Clinical data at the time of echocardiography were gathered from electronic medical records. Venous blood was collected in the morning after a 12-h fast with the patients in the sitting position to measure plasma aldosterone and renin on the same day as the echocardiography. Plasma aldosterone concentration (ng/dL) was measured by radioimmunoassay . Plasma renin activity was measured by radioimmunoassay of angiotensin I in the presence of reagents that inhibit angiotensin I–converting enzyme and angiotensinases. The assay was performed according to the method of Sealey using gammacoat plasma renin activity radioimmunoassay kits .Peripheral SBP and DBP measurements were performed automatically  at the brachial artery of the non-dominant arm in a relaxed seated position. Two BP measurements obtained at an interval of 5 min during the same visit were averaged. Central hemodynamics and parameters were assessed with pulse wave analysis of the radial artery using commercially available radial artery tonometry  , 8. The 2 for men and > 95 g/m2 for women). From the apical window, mitral inflow velocities were traced, and the following variables were obtained: peak velocity of early diastolic mitral inflow (E), late diastolic mitral inflow (A), and deceleration time of the E velocity. Early diastolic mitral annular velocity (e’), late diastolic mitral annular velocity, and systolic mitral annular velocity (S′) were measured from the apical four-chamber view with a 2- to 5-mm sample volume placed at the septal corner of the mitral annulus.Each patient underwent a comprehensive transthoracic echocardiographic study using a Vivid 7 or Vivid 9 cardiovascular ultrasound system , equipped with 2.5–3.5 MHz phased-array sector probes. Standard 2D and Doppler measurements were performed according to the recommendations of the American Society of Echocardiography guidelines . LV hypeThree consecutive cardiac cycles were recorded and averaged, and the frame rates were set to 60–80 frames/s. The analysis was performed offline using customized software . The endocardial border of the LV was manually traced from three apical views  to obtain LV global longitudinal strain of endocardial (GLS-endo), transmural (GLS-trans), and epicardial strains (GLS-epi) by averaging all regional peak longitudinal strains. Layer-specific LV global circumferential strain (GCS) was obtained from averaging all circumferential strains from the short axis view of the mitral valve, papillary muscle, and LV apex level . LV Torsion was automatically calculated as the instantaneous difference between LV apical and LV basal rotation.The global longitudinal strain of the LA (LA-GLS) was measured by manually tracing the LA endocardial border in both four-chamber and two-chamber views. Because two segments of the LA roof demonstrated lower longitudinal strain curves than the other four, they were excluded from both 4-chamber and 2-chamber views. Therefore, global peak LALS during ventricular systole was measured by averaging the values obtained in the eight other LA segments. The time to peak LALS was also measured as the average of the eight segments and by calculating the time delay from the QRS to the positive peak LALS .To examine intraobserver and interobserver variability for layer-specific LV GLS and GCS, the same observer and a second independent observer repeated the analysis of the first 10 consecutive patients. Intraobserver and interobserver intraclass coefficients were as follows: 0.97  and 0.96 (95% CI 0.96–0.98) for LV GLS-endo; 0.96 (95% CI 0.93–0.98) and 0.95 (95% CI 0.90–0.99) for LV GLS-trans; 0.93 (95% CI 0.78–0.96) and 0.89 (95% CI 0.64–0.95) for LV GLS epi; 0.93 (95% CI 0.90–0.98) and 0.95 (95% CI 0.92–0.98) for LV GCS-endo; 0.96 (95% CI 0.93–0.98) and 0.94 (95% CI 0.89–0.98) for LV GCS-trans; 0.91 (95% CI 0.75–0.96) and 0.88 (95% CI 0.62–0.95) for LV GCS epi; 0.88 (95% CI 0.84–0.92) and 0.90 (95% CI 0.85–0.95) for LA GLS.Continuous variables are presented as mean ± SD and categorical variables are presented as absolute and relative frequencies (%). Spearman’s simple correlation analyses were performed to determine the associations between strain parameters and parameters of arterial stiffness and log aldosterone. Multiple linear regressions were performed to determine the independent association of LV mechanical parameters with arterial stiffness and neurohormone.2 ± 7.9) and E/E’ value (10.4 ± 3.5) were in the normal range. The mean value of LV GLS-trans was −16.9 ± 2.9, which was slightly lower than the normal value [Table al value .Table 1Br = 0.169, p = 0.046) and LA GLS . PWV showed significant correlation with LV GLS-endo even in patients without LV hypertrophy and LV GCS-trans , whereas no significant correlation was observed with LV GLS of any layer. Unlike the correlation between LV GLS-endo and PWV, log aldosterone did not show a significant correlation with LV GCS-endo in patients without LV hypertrophy  and LA GLS  were independently correlated with PWV, even after controlling for confounding factors such as age, gender, body mass index, presence of diabetes mellitus, LV mass index, LV ejection fraction, and use of renin aldosterone angiotensin (RAAS) blockers (Table Multiple regression analysis revealed that LV GLS-endo (beta = 0.223, rs Table .Table 4DThis study presents correlation of LA and LA mechanical function with increased arterial stiffness and neurohormone level in patients with early hypertension without clinically apparent target organ damage. The principle finding from our results is that LV GLS, especially endocardium, and LA GLS were dominantly affected by central arterial stiffness in early hypertensive patients without clinically apparent target organ damage.Two-dimensional speckling analysis provides sensitive assessment of mechanical function of LV and LA. Recently, LV GLS gained clinical significance in patients with hypertensive heart disease. Lee et al. showed that LV GLS, especially that of the epicardial layer, was the only independent predictor of events . Saito eIn addition, LA GLS showed independent correlation with PWV. Although current guidelines recommend assessment for presence of LV hypertrophy as a sign of target organ damage, increased LA size is strongly associated with the duration and level of systolic blood pressure . Change The renin-aldosterone system is reported to cause subendocardial fibrosis and stimulate hypertrophy of myocytes , 20. In Early detection of cardiac structural changes in early hypertension is important with regard to risk stratification. Based on the findings from our study, LV and LA remodeling in early hypertension can be hypothesized as outlined in Fig. Several limitations of this study need to be noted. First, we included patients with early hypertension. Patients with LV hypertrophy represented only 27% of our cohort, and the small number of patients with LV hypertrophy might have affected the correlation analysis of the LV hypertrophy subgroup. Second, 51% of our patients were on RAAS blockers, which might have affected reverse remodeling of LV. However, we included use of RAAS blocker in multivariate analysis to minimize confounding effects. Third, because of the cross-sectional design of our study, we could not determine whether treatment of HTN can reverse abnormal LV mechanics. All of these issues are relevant and should be examined in future studies.Central arterial stiffness was independently correlated with LV GLS, especially endocardium, because the endocardium is the most susceptible to pressure overload among the three myocardial layers. Also, central arterial stiffness showed an independent negative correlation with LA GLS. Aldosterone showed significant positive correlation with LV GCS, especially endocardium from simple correlation, however, failed to remain significant in multivariate analysis. Different correlations between strain parameters and central arterial stiffness or aldosterone suggest different functional adaptations of LV and LA to arterial stiffness and neurohormone. In addition, two-dimensional layer-specific speckle-tracking echocardiography sensitively detected LV and LA mechanical adaptation in early hypertension, even without LV hypertrophy, and provided pathophysiologic insights into LV and LA remodeling in association with central stiffness.


To test this hypothesis, myocardial T2*-mapping was conducted at 7.0 Tesla to enhance T2*-contrast. 2D CINE T2*-mapping was performed in healthy controls and HCM patients. To ensure that T2* is not dominated by macroscopic magnetic field inhomogeneities, volume selective B0 shimming was applied. T2* changes in the interventricular septum across the cardiac cycle were analyzed together with left ventricular radius and ventricular septal wall thickness. The results show that myocardial T2* is elevated throughout the cardiac cycle in HCM patients compared to healthy controls. A mean septal T2* = 13.7 ± 1.1 ms  was observed in healthy controls. For HCM patients a mean septal T2* = 17.4 ± 1.4 ms  was found. Our preliminary results provide encouragement that assessment of T2* and its changes across the cardiac cycle may benefit myocardial tissue characterization in HCM.Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the myocardium and bares the risk of progression to heart failure or sudden cardiac death. Identifying patients at risk remains an unmet need. Recognizing the dependence of microscopic susceptibility on tissue microstructure and on cardiac macromorphology we hypothesized that myocardial T Epidemiological studies estimated the prevalence of HCM to be about 0.2–0.5% in the general population2. The disease is characterized by myocardial hypertrophy in absence of an obvious extrinsic cause such as pressure or volume overload3. Patients often remain asymptomatic, but the disease can have a severe outcome in a subgroup of patients where it may cause heart failure and unexpected sudden cardiac death (SCD) in any age group. Major basic research efforts and clinical science activities are underway to better characterize HCM patient populations4.Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the myocardium7. Vigorous research has resulted in an enormous body of literature that documents the merits of CMR and showed that the degree of hypertrophy or presence of myocardial fibrosis are associated with a poor outcome in HCM11. Notwithstanding this success, understanding the pathophysiologic mechanisms of the imaging findings and identifying patients at risk of SCD or progression to heart failure remains an unmet clinical need4. So far it has been extremely challenging to connect the molecular and cellular defects that characterize HCM to the level of major organ systems at which they play themselves out.Cardiovascular magnetic resonance (CMR) imaging has emerged as an indispensable tool in the diagnosis and risk stratification of HCM2* provides valuable means for myocardial tissue characterization without the need for exogenous contrast13. A growing number of reports refers to mapping T2* in basic research and emerging clinical CMR applications15. Myocardial T2* is commonly assumed to provide a surrogate for myocardial tissue oxygenation14. Yet, the factors influencing T2* are of multiple nature16. Further to blood oxygenation, blood volume fraction per tissue volume, hematocrit, the oxyhemoglobin dissociation curve, main magnetic field inhomogeneities, tissue pH, tissue susceptibility, tissue iron content and tissue microstructure or micromorphology were reported to govern T2* 18. Cardiac macromorphology including ventricular radius and ventricular wall thickness constitutes another category of physiological parameters that orchestrate T2* 19.Quantitative mapping of the effective transversal relaxation time T0 ≥ 7.0 T) CMR conceptually appealing for myocardial T2* mapping21. The enhanced susceptibility effects at 7.0 Tesla (T) may be useful to lower the detection level and to extend the dynamic range of the sensitivity for monitoring T2* changes19. Moving to ultrahigh magnetic fields also enables cinematic T2* mapping in scan times feasible for breath held acquisitions22. Taking advantage of this gain, temporally resolved T2* mapping at 7.0 T showed cyclic changes of myocardial T2*, demonstrated a close correlation with myocardial wall thickness and myocardial wall stress and suggested an association with alterations in myocardial blood volume fraction across the cardiac cycle23. These findings hold the potential to exploit T2* mapping for non-invasive probing of myocardial (patho)physiology in vivo24.The linear relationship between magnetic field strength and microscopic susceptibility effects renders ultrahigh field  and six patients with confirmed HCM , BMI = 25.2 ± 1.9 kg/m2) were included in the study . In vivo studies were approved by the local ethical committee. The diagnosis of HCM was based on clinical parameters including echocardiography3. Informed written consent was obtained from each volunteer prior to the study in compliance with the local institutional review board guidelines. All experiments were performed in accordance with the Declaration of Helsinki and the local institutional review board guidelines.Six healthy volunteers without any known history of cardiac disease , BMI = 23.9 ± 2.9 kg/m27. For this purpose a 3.0 T MR system  was employed using a 32-channel RF receive array. LGE images were acquired 10–15 minutes after application of gadobutrol (0.2 mmol/kg body weight) using a FLASH inversion recovery gradient echo technique to detect fibrosis. Imaging parameters were: TE = 5.4 ms, TR = 10.5 ms, flip angle 30°, spatial resolution (1.5 × 1.5 × 6.0) mm3. LGE imaging at 3.0 T was performed for five of the six patients. For the sixth patient LGE imaging data were available from a 1.5 T system . The slice planning during the current study was based on the previous clinical exams and carefully adjusted to achieve the same slice positioning.All HCM patients included in the study had previously undergone a clinical MRI exam including LGE imaging for detection of myocardial fibrosis2* and to ensure that T2* is not dominated by macroscopic magnetic field inhomogeneities but rather governed by microscopic susceptibility effects, volume selective B0 shimming was carefully carried out prior to T2* mapping23. A B0 field map was acquired in a single breath hold in end-diastole using an axial stack of slices covering the entire heart. A cardiac triggered multi-echo gradient-echo technique  mm3, 18 slices) was employed. Based on this field map second order shimming was applied for a shim volume accommodating a four chamber view and a mid-ventricular short axis view of the heart23. This shimming approach yielded magnetic field homogeneity in the heart comparable to what has been reported at 3.0 T22.To minimize the influence of macroscopic magnetic field inhomogeneities on T28. An MR stethoscope 29 and pulse oximetry were employed for cardiac triggering and gating.Experiments were performed in a 7.0 T whole body MR system . A 16 channel transceiver RF coil array was used2* mapping was performed with a segmented multi-shot multi breath hold gradient echo technique22 using: TE = 2.04–10.20 ms, ΔTE = 1.02 ms, TR = 12.16 ms, spatial resolution (1.1 × 1.1 × 4.0) mm3, flip angle 20°, GRAPPA acceleration factor 4. T2* weighted CINE acquisitions were split in three sub-acquisitions, each acquired in one breath-hold22  were used as anatomic reference. Mid-ventricular short axis views were acquired.High spatial resolution CINE Td22 Fig. . High bl2* fitting, all T2* sensitized images were de-noised using a spatially adaptive non-local means (SANLM) filter31 (VBM8 toolbox (http://dbm.neuro.uni-jena.de/vbm8/)). SANLM filtering decreased the estimated fit standard deviation of T2* in the myocardium by approximately 32% in healthy volunteers and 46% in patients in comparison to fits from unfiltered images. No artifacts due to filtering were observed in the fitted maps31. After de-noising, the T2* weighted CINE images from the three breath holds were co-registered employing a non-rigid registration provided by the MIRT MATLAB toolbox (https://sites.google.com/site/myronenko/research/mirt). Images of the three registered scans were combined to form multi-echo series covering nine echoes with increasing T2* weighting  was estimated32. Voxels with decreased fit quality (R2 < 0.7 or T2*-STD > 3 ms) or unnaturally high/low T2* (T2* ≤ 1 or T2* ≥ 50 ms) were considered unreliable and excluded from further analysis.Data processing Fig.  was perfing Fig. . Subsequdel Fig. . Goodnes2* and mean wall thickness were calculated for each cardiac phase to allow assessment of temporal changes. For this purpose only the anteroseptal and inferoseptal segments33  were considered, because T2* measurements have been shown to be most reliable in the ventricular septum20  myocardium was manually segmented for all cardiac phases. LV wall thickness and inner radius were calculated for 2.5° wide radial sections covering the whole myocardium. This procedure was executed for all cardiac phases resulting in a total sample size of 18720 sections for the healthy controls and in 17712 sections for the HCM patients. Median Tm20 Fig. . Mean in34 and MATLAB. Continuous data are expressed as mean ± SD. Group differences were analyzed for significance using a student’s t-test for normally distributed data and a Mann-Whitney u-test otherwise. Normal distribution was verified using a Shapiro-Wilk test. P values of P < 0.05 were considered significant.Statistical analysis was performed using RThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.P = 0.04). No significant differences in left ventricular end-diastolic volume (LVEDV) (P = 0.64), left ventricular end-systolic volume (LVESV) (P = 0.85) and left ventricular ejection fraction (LVEF) (P = 0.47) were found.All scans could be performed without any complication. Mean examination time for the assessment of cardiac morphology was 22 ± 7 minutes in healthy volunteers and 21 ± 2 minutes in patients. Ample blood myocardium contrast with a contrast-to-noise-ratio of about 55, image sharpness and signal uniformity across the heart were achieved for all subjects. Mean septal wall thickness (SWT) averaged over all subjects for all cardiac phases was found to be 7.3 ± 1.2 mm in healthy controls and 14.1 ± 2.5 mm in HCM patients. For end-systole mean SWT was 9.8 ± 1.4 mm in healthy controls compared to 16.6 ± 1.8 mm in HCM patients . B0 shimming resulted in macroscopic field dispersions of ΔB0 < 3 Hz per mm (in-plane) and ΔB0 < 1 Hz per mm (through-plane) in the ventricular septum which is similar to what has been previously reported for cardiac MRI at 7.0 T and 3.0 T indicating, that T2* was not dominated by macroscopic magnetic field variations23.All volunteers and patients tolerated the breath-hold 2D CINE T2* over all healthy controls for all cardiac phases  revealed a mean T2* = 13.7 ± 1.1 ms  of T2* over the cardiac cycle was 4.0 ± 1.2 ms which is significantly higher (P < 0.01) than the 0.7 ± 0.4 ms T2* change attributed to the periodic macroscopic B0 variation23.Averaging T2* over all HCM patients and for all cardiac phases  revealed mean septal T2* = 17.4 ± 1.4 ms  of T2* over the cardiac cycle compared to controls (T2*(max-min) = 3.8 ± 1.2 ms).In comparison, averaging Tms Table  which wa2* and mean inner ventricular radius over the cardiac cycle for HCM patients and healthy controls. Cyclic T2* changes across the cardiac cycle were found. A T2* increase during systole which is paralleled by an increase in the SWT and a decrease in the left-ventricular radius was observed for healthy controls and HCM patients. Also a decrease of T2* during diastole was noted for healty controls and for HCM patients. The overall shape of the curves was similar for patients and controls, with the the diastolic T2* decrease being less pronounced in patients. Plotting mean septal T2* against mean septal wall thickness revealed two clearly separable clusters for HCM patients and normal controls  has been described in HCM in the literature2* mapping at high and ultrahigh fields. While careful B0 shimming is certainly of high importance for this, in fact, dedicated shimming techniques have been shown to provide B0 field uniformities in the heart at 7.0 T similar to what has been described at 3.0 T23. Further to this, an often overlooked benefit of performing T2* mapping at higher fields is the possiblity to invest the signal gain due to the higher net magnetization to realize smaller voxel sizes. This effectively reduces intravoxel dephasing due to macroscopic field gradients and their influence on T2* and also decreases partial volume effects. The voxel size used for T2* mapping in this study of (1.1 × 1.1 × 4.0) mm3 is multiple times smaller than voxel sizes commonly used for T2* mapping in at 1.5 T ot 3.0 T which further helps to reduce the impact of macroscopic field inhomogeneities22.It is no secret that the increase of magnetic susceptibility effects at higher fields not only affects microscopic susceptibility changes of (patho)physiological origin but can also result in stronger macroscopic field distortions e.g. at air-tissue interfaces. This is often a concern about T2* increase and further analyze the temporal behavior of T2* over the cardiac cycle in health and in the presence of pathology.While we recognize a limitation due to the limited number of healthy subjects and patients studied, we believe this feasibility study to be an essential precursor to a larger 7.0 T study involving healthy and HCM patient cohorts. Such a study is needed to further elucidate the underlying causes for the reported T2* across the cardiac cycle, but the technique holds the promise to enable further insights into myocardial (patho)physiology in vivo. Admittedly, the continuous motion of the myocardium currently limits temporal T2* assessment to larger regions of interest like the septum which have to be defined for each cardiac phase. Application of motion compensation techniques to CINE T2* mapping data would enable us to derive information on T2* dynamics at single voxel level. Parameters like T2* temporal standard deviation, slope, time to peak, relative T2* change, etc. could be derived from such times series and converted to quantitative maps that may help to highlight areas of change and pathology. This approach provides an entirely new set of potential (patho)physiological imaging paramters but requires further efforts to be implemented and evaluated.We are only beginning to understand the meaning of the dynamics of T2* is elevated throughout the cardiac cycle in HCM patients compared to healthy controls at 7.0 T. A reduction in tissue blood volume fraction in the hypertrophied myocardium and a T2 increase related to inflammatory processes were suggested as potential causes for this finding. These factors have been associated with a higher risk for a poor outcome of HCM patients. Our preliminary results provide encouragement, that assessment of T2* and its changes across the cardiac cycle may benefit myocardial tissue characterization in hypertrophic cardiomyopathy.Myocardial T


A high degree of noncompacted (trabeculated) myocardium in relationship to compact myocardium (NC/C ratio >2.3) as measured by cardiac MR (CMR) has been associated with a diagnosis of left ventricular noncompaction (LVNC). However, a large proportion of healthy individuals fulfill the criterion of a LVNC; thus, the clinical significance of hypertrabeculated myocardium remains unknown. Purpose of this study was to determine if regional myocardial function and diffuse myocardial fibrosis are associated with the degree of LV trabeculation in a general population based cohort.The NC/C ratio was measured on steady-state free precession cine images in subjects from the Multi-Ethnic Study of Atherosclerosis "MESA5" follow-up cohort, free of clinical cardiovascular disease at baseline. Participants with myocardial scar on late-gadolinium enhancement imaging were excluded. Myocardial strain was measured as peak regional systolic circumferential shortening (Ecc) derived from CMR tagging images. LV myocardial T1 relaxation time, native and 12 and 25 min post contrast were determined by the T1 mapping technique and served as surrogate markers of myocardial fibrosis.The association of LV trabeculation with strain (n = 1425 subjects) and T1 time (n = 1038 subjects) was assessed by linear regression in univariate and multivariate models adjusted for demographic variables, traditional cardiovascular risk factors and CMR measures of LV volume and function.Mean, minimum and maximum NC/C ratio of all 9921 segments measured were 0.95, 0 and 5.4, respectively.There was no association of the average NC/C ratio with global (average) Ecc in a per subject analysis in univariate and multivariate models (p > 0.05). In regional analysis, there was no association of the NC/C ratio with Ecc for the midventricular LV (p > 0.05) but a higher NC/C ratio was associated with a lower Ecc (i.e. better function) for the apical LV region in univariate analysis . However, the association did not persist in adjusted models (p > 0.05).In univariate analysis a higher average NC/C ratio was associated with a higher native T1 time  but this did not persist in the adjusted models (p > 0.05). Uni- and multivariate analysis did not show an association between degree of trabeculation and T1 time measured at 12 or 25 min after contrast administration (p > 0.05).In a large population based cohort in individuals with a wide range of trabeculated myocardium, there was no consistent relationship between noncompacted myocardium as measured by the NC/C ratio and regional myocardial function or diffuse myocardial fibrosis. The absence of regional myocardial dysfunction or fibrosis may thus have the potential to discriminate patients with noncompaction from normal individuals with normal variant hypertrabeculation.


The main aim of this study was the formula application of the superficial area of a truncated prolate spheroid (TPS) in Cartesian coordinates in obtaining a cardiac parameter that is not so much discussed in literature, related to the left ventricle (LV) surface area of the human heart, by age and sex. First we obtain a formula for the area of a TPS. Then a simple mathematical model of association of the axes measures of a TPS with the axes of the LV is built. Finally real values of the average dimensions of the humans LV are used to measure surface areas approximations of this heart chamber. As a result, the average superficial area of LV for normal patients is obtained and it is observed that the percentage differences of areas between men and women and their consecutive age groups are constant. A strong linear correlation between the obtained areas and the ventricular volumes normalized by the body areas was observed. The obtained results indicate that the superficial area of the LV, besides enabling a greater knowledge of the geometrical characteristics of the human LV, may be used as one of the normality cardiac verification criteria and be useful for medical and biological applications. The human heart possesses four chambers: right atrium, left atrium, right ventricle, and left ventricle (LV). The right atrium receives deoxygenated blood and pumps it to the right ventricle, which compresses itself, pumping the blood toward the lungs, where it is oxygenated and, thus, it returns to the heart, coming in by the left atrium, and then it is moved to the LV, which, on its turn, compresses itself, forcing the blood to flow to all the body's arteries, in order to oxygenate the cells and withdraw their impurity .Due to its big influence on the general functioning of the heart, many diagnoses of diseases are based on determinations of cardiac parameters related to the LV. Because of its high capacity of presenting adaptive answer to a series of physiopathological processes and cardiovascular diseases, such as chronic renal failure, hypertension, and heart disease, the LV has become the focus of many researches for the improvement of the existing methods and obtainment of new methods of normality verification and heart disease diagnoses , 3.Some of the main cardiac parameters for the LV, which allow verifying the normality of the heart function, are as follows: ventricular volume, ejection fraction, shortening fraction, and ventricular mass. Generally, they are based on the fact that this chamber possesses a similar geometry to the ellipsoid of revolution, or, still, to a truncated prolate spheroid (TPS), implying that two of its axle shafts must have equal measures –9.Once the blood volume ejected by the LV and its structural composition is essential to the good functioning of the heart, it is natural that the parameters related to volume and mass, as already mentioned, are the focus of scientific researches.The surface area of the LV and other heart chambers is a cardiac parameter rarely discussed in the literature. Feng et al.  presenteF and E, respectively, and of the axle shafts a > b > c > 0.In Krajcik and McLenitham , 1) is  is 1) isc > a = b = r > 0, as it is seen in , which is the main focus of this research, and also, to compare the results with the ones described in , we deduZX, centered in the origin  ∈ Ω =  × .Take also the line x on function of z, which represents the part of the truncated ellipse, where x(z) ≥ 0.From  it is poZ, a TPS is obtained, once its axle shafts will be a, b, and c, with c > a = b and σ ≤ z ≤ c.Thus, when performing the revolution of the curve given by  around aAσ(S) area of the surface described in From  we have = 306.73 cm2. Taking the particular case, in which σ = −2, and with the same axle shafts, this prolate spheroid can be considered as the junction of two TPSs, obtained through the cut generated by plane z = −2, as highlighted in Consider a prolate spheroid of axle shafts σ = 2. Therefore, when we use  and shows the validity of  and the short axis (D), a, b, c, and σ measures of the TPS from measure D, which is easily obtained in echocardiographic or nuclear tests.Two important cardiac parameters of the LV are as follows: the measure of theD, once it is being considered as a TPS , which allows writing thatIn as a TPS . BesidesL and D determines the origin of plane ZX. Therefore, the largest portion generated in L division will represent the measure of the largest c semiaxis, and the other portion will represent |σ| measure. Of course, as L > c, whenever σ < 0, according to what is described in Schiller et al.  parameter, we have that D/L = δ, so In normal patients,  to 0.62 . Assuminσ| and c in function of D, if only we take ,,σ| and cD, we obtain the values of |σ| and L; consequently, the values of the TPS axle shafts, a and c, are obtained. From these measures and (Aσ(S) parameter, related to the LV surface area of normal patients.With the values of ures and , we can Dd) and the end-diastolic volume normalized by the body area (Vdn) in 107 normal individuals (asymptomatic and without cardiopathies).Macedo et al.  carried a by , a, aδ parand using , it is pδ ∈ , three values for δ were used: both ends of the interval and also 0.50, which is one of the relations most used in methods that calculate ventricular mass [σ| and Aσ(S) parameters are presented in During the simulations performed for the actual medical values of the short axis, once in healthy patients we have lar mass . The aveδ = 0.45 consists of 145.40 cm2 which is only 3.71% shorter than the area obtained in [2. For men between 20 and 29 years, this difference is practically null, once the area of 151.39 cm2 was obtained. To the other age groups, the values are also relatively close to the one of [δ = 0.50, specially to total average and to age groups until 49 years. For δ = 0.62, the value which is closer to Feng's result was for age groups of 30 to 39 years and for 40 to 49 years, with areas of 116.83 cm2 and the percentage difference of 22.63%.The total average surface area obtained for men with ained in , of 151 e one of . Good apδ = 0.45 and to the age group of 30 to 39 years, in which the percentage difference is of 3.71%.We noticed, for women, a closer approximation in relation to the result of  to the sδ studied.Yet, it is noticed that the values obtained for the LV surface area in healthy male patients are approximately 13.47% higher than the values obtained for female patients, in whatever the three cases of δ considered, however, with different values for each age group. We highlight that the major percentage difference observed is the fact that the male LV has an average surface area of approximately 34.5% greater than the female LV for age group of 40 to 49 years.For the age groups separated by sex, this characteristic was kept, as well as to the three values of These constant percentage differences for the same age groups may indicate an important and interesting characteristic on the surface areas of the LV of men's and women's heart, allowing a greater geometric knowledge of the LV and can be used as one of the verification criteria of heart normality.R2 = 0.9623 and a positive strong correlation of r = 0.9810, for all of the three simulated values of δ  parameter may also be applied in carrying out the Partial Left Ventriculectomy (PLV), which is a surgical procedure based on the resection of a slice of the LV free wall from patients with dilated cardiomyopathy in an advanced stage, so that the LV diameter can be reduced and the systolic function can be restored. This surgical procedure had its performance drastically reduced worldwide, but, on the other hand, it has been performed with strict criteria of selection, especially in Japan, and one of the problems in its realization is the lack of determination methods of the dimensions of the slice to be removed [ removed , 23. Rec removed , 24, 25.Another possible application of this parameter is in the artificial organs development, where data relating to the surface area of cardiac chambers and heart, as a whole, can be considered while determining conditions to stop the growth of the extracellular matrix, so that the artificial heart developed has the specific characteristics of each patient –28.In this work the demonstration of the formula to obtain the surface area of a TPS in Cartesian coordinates has been done, in order to associate its parameters with dimensions of axes of human LV. This type of modeling has an advantage over the modeling in ellipsoidal coordinates, once the dimensions needed to feed the model are linear and easy to obtain in more common exams, such as echocardiography.Considering the resemblance of the LV and a TPS it was possible to obtain approximations of the LV's average surface in asymptomatic patients, verifying that, for the analyzed data, the percentage difference for surface areas of LV remained constant between men and women in age group of 20 up to above 60 years. These results are new and may be applied in many areas. In particular, they may be considered as new verification criteria of cardiac normality, be used to determine the dimensions of the cardiac slice to be removed during PLV, and also be used in developing artificial organs.The work of Feng et al.  presentsThe strong correlations found between average areas and normalized diastolic volumes, for men and women, indicate that it may be possible to estimate one of these parameters, from the other one. In other words, a direct linear relation between them may exist.However, a more detailed study is needed, with a higher number of patients, individually analyzed, aiming to verify if it is possible to better adjust the values of calculated areas and improve the correlations and the obtained significance levels. Thus, the obtained values and their characteristic of variations from a type of patient to another will be more accurate, allowing a greater success in its medical and biological applications.


Gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) is a paramagnetic hepatobiliary magnetic resonance (MR) contrast agent. Due to its OATP1B1/B3-dependent hepatocyte-specific uptake and paramagnetic properties increasing evidence has emerged to suggest that Gd-EOB-DTPA-enhanced MRI can be potentially used for evaluation of liver function. In this paper we compare the diagnostic performance of Gd-EOB-DTPA-enhanced relaxometry-based and commonly used signal-intensity (SI)-based indices, including the hepatocellular uptake index (HUI) and SI-based indices corrected by spleen or muscle, for evaluation of liver function, determined using the Indocyanin green clearance (ICG) test. Simple linear regression model showed a significant correlation of the plasma disappearance rate of ICG (ICG-PDR) with all Gd-EOB-DTPA-enhanced MRI-based liver function indices with a significantly better correlation of relaxometry-based indices on ICG-PDR compared to SI-based indices. Among SI-based indices, HUI achieved best correlation on ICG-PDR and no significant difference of respective correlations on ICG-PDR could be shown. Assessment of liver volume and consecutive evaluation of multiple linear regression model revealed a stronger correlation of ICG-PDR with both (SI)-based and T1 relaxometry-based indices. Thus, liver function can be estimated quantitatively from Gd-EOB-DTPA–enhanced MRI-based indices. Here, indices derived from T1 relaxometry are superior to SI-based indices, and all indices benefit from taking into account respective liver volumes. Quantitative evaluation of liver function in clinical routine is crucial for both monitoring patients with chronic liver disease and preoperative assessment of hepatic functional reserve in patients undergoing major liver resection. To date, the evaluation of biochemical blood parameters and clinical scoring systems like the Model for End-Stage Liver Disease (MELD) score or Child- Pugh Score as well as the preoperative liver volumetry is used for assessing liver function and for selecting appropriate patients for liver surgery12®, Bayer Healthcare, Berlin) is a paramagnetic hepatobiliary magnetic resonance (MR) contrast agent for T1-weighted imaging78Gadoxetic acid Several previous studies have shown that patients with impaired liver function or advanced liver fibrosis presented with decreased liver parenchymal enhancement and a relationship between various biochemical and clinical parameters indicating liver function and signal- intensity (SI)-based measurements after Gd-EOB-DTPA administration has been demonstrated. Here, for signal intensity measurements, the relative enhancement of the liver as well as various SI ratios, corrected by signal intensity of spleen or muscle have been used10111213141516However, SI measurements provide relative parameters on an arbitrary scale which can neither be compared between repeated examinations of the same patient, nor between different patients. Moreover, SI measurements are depenedent on many technical parameters like the radiofrequency amplifier and the used receiver coils20Providing absolute, comparable parameters, the evaluation of T1 relaxation time is an alternative approach to the direct measurement of SI and has recently received augmented attention as a diagnostic tool for quantitative evaluation of liver function. Few studies have demonstrated that Gd-EOB-DTPA-enhanced MR imaging using T1 Relaxometry can be helpful for estimating liver function according to the MELD score or Child-Pugh score in patients with chronic liver disease or cirrhosis121922The purpose of this study was therefore to compare the diagnostic performance of Gd-EOB-DTPA-enhanced T1 relaxometry and commonly used SI-based indices for evaluation of liver function, determined using the ICG test and Child-Pugh Score.Patient characteristics stratified by the Child-Pugh score are summarized in Mean liver volume was significantly higher in normal liver patients and patients with Child Pugh A compared to patients with Child-Pugh B . Furthermore the mean age was significantly lower in case of NLF than in patients with Child Pugh A and B, respectively  .No significant difference was found for the other demographic variables between the patients with different Child Pugh scores.Stratified by the Child-Pugh Score, SI measurements as well as the reduction rate of T1 relaxation time (rrT1) and ΔR1 were lower for patients with reduced liver function showing a constant significant decrease with progression of liver cirrhosis . Patients with normal liver function as well as patients with increasingly impaired liver function were correlated with ICG-PDR (r = 0.89). With increasing progression of liver cirrhosis score, a significant decrease of ICG-PDR could be shown. Signal intensities and T1 values for all patients stratified by the Child-Pugh score are shown in The predictive power of respective liver function indices on ICG-PDR was analyzed.All Gd-EOB-DTPA-enhanced MRI-based liver function indices using signal intensities of liver before and 20 min after Gd-EOB-DTPA administration as well as SI-indices corrected by spleen or muscle correlated significantly with ICG-PDR  was calculated and multiple linear regression models for all SI-based liver function indices, including LV as an additional covariate, were constructed. Since LV is part of the HUI, it was included in the linear regression model. In this model, HUI correlated significantly with ICG-PDR (r = 0.735)  and reveFor multiple regression analysis, again, the optimal curve fit for ICG-PDR was a log-linear relationship and the best predictor among SI-based liver function indices was obtained by considering the liver-to-spleen ratio and respective liver volumes (r = 0.767) .All SI-based liver function indices revealed better correlation with ICG-PDR taking into account respective liver volumes in multiple regression analysis  of the liver correlated most strongly with the ICG-PDR among all Gd-EOB-DTPA-enhanced MRI-based liver function indices.The correlation of rrT1 and ΔR1 with ICG-PDR was investigated. The optimal curve fit for ICG-PDR was a log-linear relationship with r = 0.829 and 0.784, respectively . A betteT1-weighted VIBE sequences and colour-coded T1 maps for patient with normal and impaired liver function are shown in Gd-EOB-DTPA-enhanced MRI is already used in an increasing number of patients scheduled for liver surgery allowing both delineation of tumors from liver parenchyma as well as assessment of topography with regards to intrahepatic vessels. In recent years, increasing evidence has emerged to suggest that Gd-EOB-DTPA- enhanced MRI can be potentially used for evaluation of global and remnant liver function12131518192425262728The indices that have been proposed for assessment of liver function using Gd-EOB-DTPA-enhanced MRI include both SI-based indices and T1 relaxometry. Here, SI-based indices are corrected by a variety of parameters to compensate the relative nature of an arbitrary unit, e.g. the SI before contrast media administration or the signal intensities of the spleen or muscle.In a prospective study we recently could demonstrate that Gd-EOB-DTPA-enhanced T1 relaxometry in combination with respective liver volumes might be a valuable tool for estimating liver function as determined using ICG-testHowever in the current literature, there still exists no consensus on which parameters derived from Gd-EOB-DTPA-enhanced MRI – either SI-based indices or T1 relaxometry-based indices- are the most suitable for evaluation of liver function. We therefore designed an retrospective study comparing all known MRI-based indices, which contains in parts data from our previously published study concerning T1 relaxometry values (overlap of patients: n = 174).It is important to recognize that Gd-EOB-DTPA uptake does not correlate with various clinical factors 831et al. reported a compareable correlatation between ICG-R15 and the liver-to-muscle ratio (r = 0.67)et al. revealed a weaker correlation (r = 0.319)In our study, all SI-based indices for the estimation of liver function  significantly correlated with the ICG-PDR , with the weakest correlation for the liver-to-muscle ratio (r = 0.675) and the highest correlation for the increase rate of the liver-to-spleen ratio (r = 0.733) Compared to our results, Utsunomiya et al.Using precontrast image data, individual differences of signal intensities in the liver, muscle or spleen before Gd-EOB-DTPA administration may be reduced, which should allow for precise assessement of Gd-EOB-DTPA liver parenchyma uptake. Taking into account the SI of muscle before contrast media administration, the increase rate of the liver-to-muscle ratio (r = 0.701) correlated more strongly with ICG-PDR than the liver-to-muscle ratio alone (r = 0.675) which is consistent with the results of Kamimura et al. provided a correlation coefficient of 0.528, compared to ICG-R15In the literature, few studies reported an increase rate of a liver-to-muscle ratio, also called “contrast enhancement index” (CEI)1416et al. (r = 0.457)et al. and Kamimura et al. showed weaker correlations 10While our results revealed a good correlation between ICG- parameter and the liver-to-spleen ratio (r = 0.725), which is arithmetically equivalent to the corrected enhancement of the liver-to-spleen ratio provided by Yoneyama et al.et al.Calculating an increase rate of the liver-to-spleen ratio taking into account the SI of spleen before contrast media administration, which is arithmetically equivalent to the liver-to-spleen-contrast ratios (LCS_N20) provided by Noren et al. et al. 131415In this study, the correlation  between the RE of the liver and ICG parameter (ICG-PDR) was stronger compared to the correlation coefficients in the literature provided in previous reports by Yoneyama However, MRI SI measurements reflect relative values on an arbitrary scale and depend on many technical parameters, such as the used pulse sequence, reconstruction method or MRI system manufacturer, the potency of the radiofrequency amplifiers, and the used receiver coilsIndeed, among all provided Gd-EOB-DTPA-enhanced MRI-based liver function indices, our results revealed that the reduction rate of the T1 relaxation time (rrT1) of the liver correlated most strongly with ICG-PDR (r = 0.829). The correlation was significantly higher compared to the increase rate of the liver-to-spleen ratio, which has been shown to provide the best correlation coefficient among the SI values without liver volumes .et al. showed a proportional relationship between ICG-parameters and the total hepatic parenchymal cell volumePrevious studies showed that measuring the LV is a useful tool for estimating liver function and that a decrease of the liver volume comes along with the progression of liver cirrhosis36In our study, the LV showed a weak correlation with the ICG-PDR .In a multivariate analysis, we correlated all SI-based indices and values derived from T1 relaxometry in combination with the respective liver volumes with ICG-parameters and observed significantly higher correlations for all indices compared to those without the inclusion of respective liver volume (p ≤ 0.003).et al. correlated ICG-R15 with various MRI-based liver function indices using SI measurements or T1 relaxation time; however, they did not provide higher correlations for the liver-to-spleen ratio  and the reduction rate of T1 relaxation time  by taking into account respective liver volumesYoneyama et al. introduced the hepatocellular uptake index (HUI), a corrected enhancement of the liver-to-spleen ratio multiplied by the liver volume (VL × (L20/S20) − 1). Here, the contrast enhancement effect of Gd-EOB-DTPA caused by the extracellular fluid space, which is the sum of the intravascular and extravascular spaces, is corrected by including the SI of the spleenet al. assumed a linear relationship between HUI and ICG-PDR providing a correlation coefficient of r = 0.87. However, contrary to the retention rate of ICG after 15 min , the diffusion rate of ICG (ICG- PDR) is subject to the influence of the measured timespan and the respective unit is provided in %/min. Our results revealed that the correlation between ICG-PDR and liver function indices, either SI-based or derived from T1 relaxometry, follows an exponential distribution with consecutive log-linear relationship. Therefore, Yamada et al. might have underestimated the correlation between HUI and ICG-PDR.Taking into account respective liver volumes for quantitative evaluation of liver function, Yamada In this study, among indices without involvement of respective LV, the reduction rate of T1 relaxation time showed stronger correlation with ICG-PDR (r = 0.829) compared to HUI (r = 0.735) with statistically significant difference between the correlations of rrT1 and HUI (p = 0.013). Using respective liver volumes in a multivariate analysis model, compared to HUI, all MRI-based liver function indices correlated stronger with ICG-PDR with highest values for the reduction rate of T1 relaxation time (r = 0.90), allowing for the calculation of an estimated ICG-PDR value.et al. used a three-dimensional dual-flip technique to acquire T1 maps in a spoiled gradient echo sequence lacking a B1 correction to counteract B1 heterogeneities. These reasons might contribute to the small, not significant differences between SI-based measurements and relaxometry measurements. Moreover, no histological evidence of hepatitis or liver fibrosis for most of the patients was available in our study.Our study has several limitations. First, the number of included patients was small. A stronger correlation between Gd-EOB-DTPA-enhanced MRI-based liver function indices and ICG-PDR could have been obtained if our study had included a larger number of patients. Second, only one experienced radiologist performed ROI placement and ROI placement may be a source of variation due to the potential inhomogeneous distribution of parenchymal changes. However, averaging four repetitive ROI measurements across an area of the liver parenchyma should yield representative values. Moreover, to obtain homogeneous T1 maps of the entire liver, we used a prototype three-dimensional gradient echo triple-flip angle technique with the preceding acquisition of a B1 map for inline correction of B1 inhomogeneities. Yoneyama In conclusion, liver function correlating with ICG-PDR can be estimated quantitatively using Gd-EOB-DTPA-enhanced MRI-based indices. Here, indices derived from T1 relaxometry are superior to SI-based indices, and all indices benefit from taking into account respective liver volumes. Our results indicate that Gd-EOB-DTPA-enhanced T1 relaxometry, in combination with liver volume, may have the potential to become a novel tool for monitoring liver function.Written informed consent was obtained from all participating patients and the study was performed in accordance with the relevant guidelines and regulations. The local institutional review board approval of the University Hospital Regensburg was obtained for this retrospective study.The current retrospective analysis is based in parts on a previously published patient cohort The aim and scope of the current study differs markedly compared to the previous study insofar as we have a different context of data analysis. Whilst our previously published study was a prospective study to establish a new liver function parameter based on T1 relaxometry, the current study is a retrospective comprehensive comparison and evaluation of all published MRI- based liver function tests. Thus parts of the following Materials and Methods section have a close resemblance to our previously published study, with regards to the definition of basic study parameters, i.e. imaging sequences, ICG-test, the definition of the Child Pugh Score.Retrospective analysis covered the period of time between end of August 2013 and April 2014 and included all patients who underwent both an ICG test for evaluation of liver function (n = 131) and a Gd-EOB-DTPA-enhanced MRI at 3.0 T (n = 236). To be included in the study, patients had to have undergone a Gd-EOB-DTPA-enhanced MR imaging examination with prototype T1 relaxometry sequences using variable flip angles that was performed within 24–72 h of ICG test.14 patients were excluded from this study due to the inability to complete the full MR imaging protocol due to poor breath-holding and due to images with respiratory motion artifacts or severe imaging artifacts that would not allow analysis in T1 relaxometry images .All patients had no history of previous reaction to liver-specific MRI contrast media or contraindication to both MRI  and Gd-EOB-DTPA administration in terms of no renal failure (defined as a glomerular filtration rate of less than 30 mL/min), respectively. None of the patients had a thyroid hyperfunction or an iodine allergy.Finally, 117 patients  were included in our study. 50 patients had a normal liver function (NLF) with ICG-PDR > 16.0%/min and no evidence or clinical signs of liver cirrhosis. 67 patients were assigned to the liver cirrhosis group, where diagnosis of liver cirrhosis was based on laboratory values, imaging findings and clinical findings according to the Child-Pugh Score depending on the degree of prothrombin time , serum albumin , serum bilirubin , ascites  and encephalopathy . 27 of the 67 patients with liver cirrhosis were classified with Child-Pugh A , 22 patients with Child-Pugh B , and 18 patients with Child-Pugh C . Patient characteristics are shown in All imaging was performed using a clinical whole body 3T system  and combination of spine and body array coils  was used for signal reception. Each T1-weighted volume-interpolated breath-hold examination (VIBE) sequence with fat suppression (repetition time (TR), 3.09 ms; echo time (TE), 1.16 ms; flip angle, 9°; parallel imaging factor, 2; slices, 64; reconstructed voxel size, 1.3 × 1.3 × 3.0 mm; measured voxel size, 1.7 × 1.3 × 4.5 mm; acquisition time, 14 s) was acquired during breath-hold before and 20 min after Gd-EOB-DTPA  administration. All patients received a Gd-EOB-DTPA dose (0.025 mmol/kg body weight) adapted to their body weight, which was administered via bolus injection with a flow rate of 1 mL/s and flushed with 20 mL NaCl. Every sequence covered the entire liver before Gd-EOB-DTPA administration and in hepatobiliary phase after 20 min (HBP).In addition to the routine imaging protocol, T1 mapping of the liver was performed before Gd-EOB-DTPA administration and in HBP using a prototypical VIBE sequence  using variable flip angles  and a voxel size of 3.6 mm × 2.5 mm × 4.7 mm, interpolated to 2.5 mm × 2.5 mm × 3.0 mm. A B1 map of the whole liver was acquired for each patient before T1 mapping to improve the homogeneity of the T1 maps, and color-coded T1 maps were calculated inline. The whole liver was covered in 17 s during breath-hold using an acceleration factor of 4 and CAIPIRINHA  as a parallel imaging technique.2 in liver parenchyma, 0.8–2.1 cm2 in paravertebral muscle and 2.7–4.9 cm2 in spleen. To avoid measurement bias, the radiologist was blinded to the clinical, haematological and other radiological information. From the data acquired, the following Gd-EOB-DTPA-enhanced MRI-based liver function indices using SI or T1 relaxation time before and 20 min after Gd-EOB-DTPA administration were calculated:Hepatocellular uptake index (HUI)Relative enhancement of the liver15Liver-to-spleen ratio1011Liver-to-muscle ratio10Increase rate of the liver-to-spleen ratioIncrease rate of the liver-to-muscle ratio16Reduction rate of T1 relaxation time of the liver19ΔR1 of the liverThe mean SI values on T1-weighted images of the liver, spleen and paravertebral muscle (at the hight of the liver hilum) and T1 relaxation time on T1 maps of the liver, obtained before and 20 min after Gd-EOB-DTPA administration, were measured by using operator-defined region-of-interest (ROI). ROIs were manually placed at identical locations in every sequence, excluding liver lesions, visible blood vessels, or imaging artifacts. Four ROIs  were located in VIBE images and T1 maps and one ROI was located in the paravertebral muscle and spleen, before and after administration of Gd-EOB-DTPA, respectively. The mean signal intensities and T1 values for the four ROIs in the liver were regarded as the representative SI and T1 values of the entire liver, respectively. Each ROI was a circle that was chosen as large as possible and ROIs were manually adjusted between sequences (before and after Gd-EOB-DTPA administration) in the case of patient movement. The size of the ROIs ranged from 0.9 to 4.2 cmConsidering the volumes of respective livers, volume-assisted indices of signal intensity and T1 relaxometry could be calculated using a multivariate regression analysis.To draw the outlines of the liver on every section, the delayed T1- weighted 3D VIBE sequence hepatobiliary phase was used. In this procedure, MR images were provided on an Aquarius iNtuition Viewer  on a commercially available workstation and free-hand contours were used to obtain respective liver volumes. If there was a liver tumour that was hypointense on 20-min-delayed Gd-EOB-DTPA-enhanced images, the volume of the hypointense tumour was excluded from the volume of the liver parenchyma.To determine the ICG plasma disappearance rate (PDR) the noninvasive pulse-densitometric LiMON system  was used. A bolus dose of 0.5 mg per kilogram bodyweight of ICG  was injected into a cubital vein, followed by 10 mL of normal saline flushed through the intravenous catheter, and each patient was monitored with an ICG finger clip connected to the liver function monitor (LiMON) via an optical probe. Injected ICG was detected from fractional pulsatile changes in optical absorption, and ICG elimination measurements (ICG-PDR) were determined by monoexponential transformation of the original ICG concentration curve and backward extrapolation to time point zero (100%), describing the decay as a percentage change with time.To acquire liver function within a reasonable timeframe and to eliminate any confounding with Gd-EOB-DTPA enhanced MRI, the ICG-test of patients was performed 24–72 h prior to or 24–72 h post-MRI.A one-way analysis of variance (ANOVA) was used to analyze differences in continuous variables between patients with NLF and patients with different stages of liver cirrhosis. Post hoc pair-wise comparisons were made with the Tukey procedure. Simple and multiple linear regression models were calculated to determine the predictive power of Gd-EOB-DTPA-enhanced signal intensity indices and T1-relaxometry measurements on the ICG-parameter ICG-PDR. Since ICG-PDR is an exponential transformation of the ICG-R15, which is linear related to the SI- and T1-relaxometry based liver function indices, the logarithm of ICG-PDR was used as dependent variable in all models. The optimal curve fit was assessed visually and using the coefficient of correlation r. Correlation coefficients were compared using the method proposed by Steiger. The statistical significance level was set to 0.05 (two-sided). All statistical analyses were carried out using IBM SPSS Statistics  and R 3.0.3.How to cite this article: Haimerl, M. et al. Gd-EOB-DTPA-enhanced MRI for evaluation of liver function: Comparison between signal-intensity-based indices and T1 relaxometry. Sci. Rep.7, 43347; doi: 10.1038/srep43347 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Septal and LVPW cIB and LV diastolic strain rates were determined. Patients had significantly lower DWS (p < 0.001), higher stiffness index (p < 0.001), and greater cIB (p < 0.001). LV DWS correlated negatively with LV stiffness index , septal cIB , E/e ratio  and RV end-diastolic area , and positively with LV early  and late  diastolic strain rates and RV fractional area change (FAC) . Multivariate analysis revealed E/e , RV end-diastolic area , and RV FAC  as significant correlates of DWS. Left ventricular stiffening occurs after TOF repair and is related to impaired LV diastolic myocardial deformation, myocardial cIB, and RV volume overload.Left ventricular (LV) remodeling after tetralogy of Fallot (TOF) repair may influence LV stiffness. We hypothesized that LV stiffness is altered after TOF repair and related to myocardial calibrated integrated backscatter (cIB) and LV diastolic myocardial deformation. Seventy-seven TOF patients and 80 controls were studied. LV stiffness was assessed by diastolic wall strain (DWS) as defined by (LVPW On the other hand, increasing evidence suggests that left ventricular (LV) dysfunction may also have prognostic significance in these patients4. Left ventricular systolic dysfunction has been attributed to several factors including preoperative hypoxaemia5, LV fibrosis7, LV dyssynchrony8 and adverse right-left ventricular interaction9. On the other hand, the phenotype and understanding of pathogenetic mechanism of LV diastolic dysfunction in repaired TOF is less clear.Right ventricular (RV) dilation and dysfunction secondary to chronic severe pulmonary regurgitation are well documented in patients late after repair of tetralogy of Fallot (TOF)11. Importantly, however, recent data suggest that potential alteration of myocardial substrates occurs in repaired TOF, which may predispose to stiffening of LV myocardium. In these patients, increased levels of circulating biomarkers of collagen synthesis have been reported13. Cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement6 and T1 mapping7 techniques has further revealed evidence of LV fibrosis. The potential consequence on LV stiffness of LV remodeling related to myocardial fibrosis and geometric eccentricity secondary to RV volume overload has, however, not been explored in patients after TOF repair.Diastolic ventricular dysfunction may be related to relaxation abnormality and/or stiffening of the myocardium. Previous studies in repaired TOF patients have primarily assessed indirectly LV early diastolic relaxation and estimated late diastolic filling using Doppler imaging14, which quantifies the thinning of myocardium during diastole, has been found to be useful in assessing diastolic myocardial stiffness and prognostication in heart failure patients with preserved ejection fraction15. Another potentially useful LV stiffness index that relates Doppler-estimated LV filling pressure to LV end-diastolic dimension has been used to interrogate myocardial stiffness in athletes16. In this study we aimed to utilize these indices to test the hypothesis that LV stiffness is altered in adolescents and young adults with repaired TOF and to determine its relationship to myocardial calibrated integrated backscatter (cIB) as a marker of fibrosis17 and LV diastolic myocardial deformation.Recently, there has been increasing use of echocardiography for non-invasive assessment of myocardial stiffness. The parameter of diastolic wall strain (DWS)15. This study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster, Hong Kong, and all of the methods as described were performed in accordance with the approved guidelines and regulations. Informed consent had been obtained from all of the participants at the time of acquisition of echocardiographic images.This was a retrospective study of our echocardiographic database of congenital heart disease that included 77 consecutively studied TOF patients post total surgical repair. The following patient data were retrieved from case notes: cardiac and associated lesions, type of operation performed, date and age of operation, and the need for additional procedures. A total of 80 age-matched healthy controls were retrieved from the healthy control database for the purpose of comparisons. These included healthy staff volunteers, their friends, and subjects with chest pain or palpitation for which no organic causes had been identified. The body weight and height of all subjects were measured at the time of echocardiographic acquisitions and the body surface area was calculated accordingly. The total number of around 80 subjects in each group gave a statistical power of 80% with 5% level of significance with two-sided testing to detect a minimum DWS difference of 0.03 with a variation of 0.08 based on the previously reported standard deviationEchocardiographic acquisitions were made using Vivid 7 ultrasound machine . Offline analyses of the recordings were performed using EchoPAC software . Measurements of all echocardiographic parameters were made in three cardiac cycles and the average was taken for statistical analyses.e), late diastolic myocardial tissue velocity (a), e/a ratio, and E/e ratio. Severity of pulmonary regurgitation was graded semi-quantitatively as mild, moderate, or severe by color flow mapping18.From the four-chamber view, RV end-diastolic and end-systolic areas were measured and RV fractional area change was calculated accordingly. Transmitral pulsed-wave Doppler examination was performed to obtain peak early diastolic inflow velocity (E), late diastolic inflow velocity (A), E/A ratio, and E deceleration time. Tissue Doppler echocardiography was performed with sample volume positioned at the basal LV free wall-mitral annular junction to obtain the peak early diastolic myocardial tissue velocity  thickness at systole and diastole was determined. Diastolic wall strain (DWS) was calculated as (LVPW at systole - LVPW at diastole)/LVPW at systolee)/LVEDd, where LVEDd is LV end-diastolic dimension derived from M-mode measurement16. This parameter was used to provide an estimate of the pressure-to-volume relationship, with LV filling measure being estimated by E/e ratio and end-diastolic LV volume being estimated by LVEDd.Stiffness index was calculated as .Left ventricular diastolic myocardial deformation in the longitudinal dimension was interrogated using speckle tracking echocardiography as reported previouslyData was expressed as mean ± standard deviation. Differences in demographic and echocardiographic parameters between repaired TOF patients and controls were compared using the Student’s t-test and Fisher’s exact test where appropriate. Relationships between LV stiffness indices and cIB and indices of LV diastolic deformation were explored using Pearson correlation analysis. Multivariate analysis using multiple linear regression was performed to determine significant correlates of DWS and stiffness index respectively with adjustments of variables having a p value < 0.05 by univariate analysis. A p value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 17.0 .2 vs 1.46 ± 0.34 m2, p = 0.14).Of the 77 patients, 72 had TOF with pulmonary stenosis, while 5 had pulmonary atresia. The patients  were aged 18.5 ± 8.1 years and studied at 14.6 ± 7.3 years after total surgical repair. Twenty patients had systemic-to-pulmonary arterial shunt palliation before total surgical repair. Of the 72 TOF patients with pulmonary stenosis, 58 required transannular patch repair of RV outflow. Pulmonary valve replacement was performed subsequently in four of the 77 patients. Six of the patients had syndromal associations including DiGeorge syndrome in 3, Down syndrome in 1, trisomy 20p in 1, and VATER association in 1. The 80 controls  were aged 16.5 ± 7.0 years (p = 0.11). Compared with controls, patients had similar body weight , body height , and body surface area (1.38 ± 0.33 mTable e velocity (p < 0.001) and global longitudinal early (p < 0.001) and late (p < 0.001) diastolic strain rates, and greater E/e ratio (p < 0.001) in patients as compared with those of controls.Worse LV diastolic mechanics in repaired TOF patients was evidenced by the significantly lower Compared with controls, TOF patients had significantly lower DWS  and higher LV stiffness index  Fig. . For theFor cIB, patients had significantly greater septal cIB , LV posterior wall cIB  and average cIB .e velocity , LV early diastolic longitudinal strain rate , RV volume load , and RV fractional area change . These were, however, no significant correlation between septal or posterior cIB and LV stiffness index.The septal but not posterior wall cIB was found to correlate negatively with LV DWS . Additionally, cIB at septum was found to correlate with mitral annular e ratio (p < 0.001) and RV end-diastolic area (p < 0.001), and positively with e velocity (p < 0.001), LV global early (p < 0.001) and late (p = 0.01) diastolic longitudinal strain rates, and RV fractional area change (p = 0.003) , RV end-diastolic dimension (p = 0.02), and RV fractional area change (p = 0.01) as significant independent correlates of DWS.Table 03) Fig. . Multivae velocity (p < 0.001), and E/e ratio (p < 0.001) based on which the parameter was derived. Additionally, stiffness index was found to correlate positively with RV end-diastolic area . Multivariate analysis identified RV end-diastolic area (p = 0.004), LV end-diastolic dimension (p < 0.001) and E/e ratio (p < 0.001) as significant independent correlates.On the other hand, the stiffness index expectedly was found to correlate with LV end-diastolic dimension (p < 0.001), transmitral E velocity (p < 0.001), mitral annular In patients, there were no significant correlations between severity of pulmonary regurgitation and DWS and stiffness index (both p > 0.05).The present study demonstrates diastolic myocardial stiffening as reflected by reduced LV diastolic wall strain and increased stiffness index in adolescents and young adults with repaired TOF. Increased myocardial stiffness was associated with worse LV diastolic myocardial deformation as characterized by slower global LV early and late diastolic longitudinal strain rates. Furthermore, our data provided evidence that myocardial fibrosis and RV volume overload might be important factors that contributed to LV stiffening late after repair of TOF. To our knowledge, this is the first study to explore LV stiffening and its possible associations with myocardial fibrosis, RV volume load, and LV diastolic myocardial deformation.11. Our findings of reduced mitral annular e velocity and global LV longitudinal diastolic strain rate are compatible with impaired LV relaxation and agree with those reported previously12. Increased LV end-diastolic pressure as documented by cardiac catheterization in repaired TOF patients, on the other hand, provides evidence of reduced LV compliance22, although data on stiffening of ventricular myocardium in these patients are lacking.There has been increasing interest on ventricular diastolic dysfunction in patients with repaired TOF. Previous studies have focused on interrogation of LV relaxation abnormalities23. Recently, the echocardiographic parameter of DWS, which reflects the change of wall thickness and resistance to deformation during diastole, has been validated in animal studies and shown to correlate inversely with the invasively determined myocardial stiffness constant14. In clinical studies, DWS has been shown to predict outcomes of patient with heart failure with preserved15 and reduced24 ejection fraction and in patients with non-ST elevation myocardial infarction25. With regard to the LV stiffness index, which provides an estimate of the relationship between LV filling pressure and end-diastolic volume, this has been reported to be useful in the demonstration of reduced myocardial stiffness in elite athletes16. Our findings of reduced DWS and concomitant increased LV stiffness index in patients with repaired TOF provide therefore evidence of LV myocardial stiffening. Importantly, the magnitude of LV myocardial stiffening was found to relate inversely to indices of LV diastolic deformation. Hence, LV diastolic dysfunction in patients with repaired TOF is attributable in part to increased stiffness of the ventricular myocardium.Direct assessment of LV stiffness is challenging and requires invasive cardiac catheterization for the derivation of the diastolic pressure-volume curve and calculation of chamber stiffness constant26, in patients with metabolic syndrome27, and in those with heart failure28. Our finding of increased cIB in repaired TOF patients are compatible with previous reports of increased levels of circulating biomarkers of collagen synthesis13 and CMR late gadolinium enhancement6 and T1 mapping7 studies demonstrating evidence of LV fibrosis in these patients. Fibrosis increases the viscoelastic burden of the myocardium and impairs relaxation, diastolic suction, and passive stiffness29. Indeed, significant associations between myocardial fibrosis and worsening of LV stiffness have been shown in heart transplant recipients30 and in patients with heart failure with preserved ejection fraction31.While the exact mechanisms of LV myocardial stiffening in our patients remain to be unveiled, the present study suggests that two factors may potentially be important. Firstly, increased cIB of the ventricular septum and LV posterior in our patients suggests that alteration of myocardial substrate with increased deposition of fibrous tissue might be a culprit. Calibrated integrated backscatter has been used to assess myocardial fibrosis in obese subjects27 and in patients with heart failure with preserved ejection fraction28. In our patients, previous cardiopulmonary bypass and surgical closure of ventricular septal defect might have accounted for our findings although this remains speculative. Notwithstanding, preferential involvement of the septum has been shown to influence adversely the degree of LV diastolic dysfunction32.Intriguingly, we found significant negative correlation between DWS and cIB of the septum but not posterior wall. Furthermore, the septal cIB difference between patients and controls was more significant than that of the LV posterior cIB difference. It is interesting to note that preferential fibrotic alteration of the septum has also been shown in patients with metabolic syndrome and LV dysfunctionet al. who found a significant relationship between RV end-diastolic volume and LV end-diastolic pressure22. Kim et al. have recently further reported using CMR LGE that non-ischaemic septal fibrosis is independently associated with RV chamber dilation and hypothesized the role of increased RV wall stress33. Additionally, reduced LV preload secondary to altered septal geometry may reduce ventricular compliance as reported similarly in patients with large atrial septal defects34.The second potentially important factor that may contribute to LV stiffness in our patients is geometric alteration of the ventricles secondary to RV volume overload. Multivariate analysis has identified RV end-diastolic area and fractional area change as independent determinants of both DWS and stiffness index. Our hypothesis is further supported by the study of Schwartz 4, the clinical implication of LV diastolic dysfunction in repaired TOF is less clear. Nonetheless, several considerations warrant comments. Left ventricular dysfunction may impact adversely on pulmonary arterial compliance35, which in turn increases RV afterload and potentially worsens pulmonary regurgitation36. This is of particular relevance in the context of repaired TOF. Utilization of a semi-quantitative method rather than cardiac magnetic resonance to quantify pulmonary regurgitation in this study, however, might have precluded the identification of an association between LV myocardial stiffness and pulmonary regurgitation. Increased LV end-diastolic pressure of 12 mmHg or more has been associated with larger right ventricles22 and shown to be strong predictor of appropriate implantable cardioverter-defibrillator shocks in patients with repaired TOF37. The inclusion of LV diastolic dysfunction when considering the timing of pulmonary valve replacement and assessment of it reversibility after valve replacement should be topics for further research.While the prognostic implication of LV systolic dysfunction in repair TOF has been documentedSeveral limitations to the study require comments. Firstly, this cross-sectional study cannot provide data on the relationship between progressive RV dilation and LV stiffening. Further longitudinal studies are required to address the serial changes in LV stiffness post TOF repair and its potential improvement after pulmonary valve replacement. Secondly, the measurement of DWS is regional, based on changes of the LV posterior wall thickness in the cardiac cycle. Heterogeneity of biomechanical properties in different myocardial regions may exist and further work to develop a more global echocardiographic index of myocardial stiffness is indicated. We have therefore also included the LV stiffness index, albeit based the estimates of LV filling pressure and size, to provide a more global assessment. It would have been ideal to be able to assess RV stiffness using similar echocardiographic measurements. However, the use of DWS to quantify RV stiffness has not been reported and yet to be validated. Finally, the use of the new CMR T1 mapping technique, which was not available at the time of study of our patients, may shed more light on the relationship between diffuse myocardial fibrosis and LV diastolic mechanics.In conclusion, LV stiffening occurs late after repair TOF repair and is related to impaired LV diastolic myocardial deformation, myocardial calibrated integrated backscatter, and RV volume overload.