The function of the right and left ventricles is intimately related through a shared septum and pericardium. Therefore, right ventricular (RV) disease in pulmonary hypertension (PH) can result in abnormal left ventricular (LV) myocardial mechanics. To assess this, we implemented novel cardiovascular magnetic resonance (CMR) tissue phase mapping (TPM) to assess radial, longitudinal and tangential LV myocardial velocities in patients with PH.n = 34) were followed up until the primary outcome of disease progression  or the end of the study. Physicians who determined disease progression were blinded to CMR data. Conventional ventricular volumetric indices and novel TPM metrics were analyzed for prediction of 6-min walk distance (6MWD) and disease progression.Respiratory self-gated TPM was performed using a rotating golden-angle spiral acquisition with retrospective cardiac gating. TPM of a mid ventricular slice was acquired in 40 PH patients and 20 age- and sex-matched healthy controls. Endocardial and epicardial LV borders were manually defined, and myocardial velocities calculated using in-house software. Patients without proximal CTEPH (chronic thromboembolic PH) and not receiving intravenous prostacyclin therapy (p < 0.0001) and radial (p = 0.001) early diastolic (E) wave velocities were significantly lower in PH patients compared with healthy volunteers. Reversal of tangential E waves was observed in all patients and was highly discriminative for the presence of PH (p < 0.0001).Peak longitudinal (p = 0.017) and lateral wall radial systolic (S) wave velocities  were the only independent predictors of 6MWD in a model including RV ejection fraction (RVEF) and LV stroke volume.The global radial E wave  in a model including RVEF and septal curvature.Over a median follow-up period of 20 months (IQR 7.9 months), 8 patients commenced intravenous therapy and 1 died. Global longitudinal E wave was the only independent predictor of clinical worsening  contains supplementary material, which is available to authorized users. Pulmonary hypertension (PH) is characterized by increased pulmonary artery pressure and right ventricular (RV) failure. Cardiovascular magnetic resonance (CMR) is the reference standard method of assessing RV function and is now routinely used in PH. Several studies have shown that CMR-derived RV volumes and ejection fraction (EF) are prognostic in this condition , 2.It has also been shown that left ventricular ejection fraction (LVEF) is reduced in late stage PH . HoweverThe most comprehensive way of evaluating LV mechanics is to assess the regional and geometric components of LV motion. There are several CMR methods that can be used to assess these metrics. In this study, we used tissue phase mapping (TPM) to assess radial, longitudinal and tangential myocardial velocities in patients with PH –13. As tThe specific aims of this feasibility study were: i) to assess global and regional LV myocardial mechanics in healthy volunteers and in patients with PH with preserved LVEF, ii) to determine the relationship between myocardial velocities and exercise capacity, and iii) to test the ability of myocardial velocities to predict clinical worsening.The study population consisted of 40 consecutive patients with PH and 20 healthy volunteers. Inclusion criteria for patients were: i) PH diagnosed by right heart catheterization (mean pulmonary artery pressure (mPAP) >25 mmHg and pulmonary capillary wedge pressure (PCWP) <15 mmHg) ; or ii) All patients underwent the CMR study between 3rd October 2012 and 24th November 2013. All participants were imaged using a 1.5T MR scanner . All patients underwent a 6-min walk distance test (6-MWD). Twenty-nine patients (73 %) underwent clinically indicated right heart catheterization within 40 days of CMR .The local institutional research ethics committee (North West London REC 2) approved the study and informed written consent was obtained from all participants.k-t SENSE real-time sequence [Biventricular volumetric data were obtained as described previously, using a radial sequence , with cosequence .All images were processed using in-house plug-ins for the open source OsiriX DICOM software platform  . Endocartwo-sided flow-encoding scheme (with positive and negative bipolar pulses applied for each velocity-encoding direction) was used to enable high temporal-resolution imaging . Data were continuously acquired, with each consecutive flow-encoding couplet rotated by the golden-angle. Consecutive spiral pairs (10 in each window) are combined to produce low temporal resolution (315 ms) real-time images. These real-time data are used to create an image based respiratory navigator, used to select 30 % of the expiratory spiral interleaves for the final retrospectively cardiac-gated reconstruction. Sequence parameters: TE/TR 3.85/14.9 ms, FOV 450 mm, Matrix: 384 × 384, uniformly distributed spiral interleaves required to fill k-space: 30 (for each of the three phase-encoded directions), slice thickness: 7 mm, VENC: 30 cm/s, Flip angle: 25°, pixel bandwidth: 930 Hz/pixel. This achieved a temporal resolution of 27.14 ms, with a spatial resolution 1.17 × 1.17 mm, giving approximately 40 cardiac phases. The nominal scan time, assuming a heart rate of 60 bpm and 100 % respiratory efficiency, would be 1 min 30 s, resulting in a scan time of approximately 4 to 5 min per subject depending upon heart rate. TPM data were acquired in mid-ventricular short-axis, which was chosen by reference to a 4-chamber cine at end-systole.Myocardial velocities were acquired using a respiratory self-navigated, cardiac gated, velocity encoded golden-angle spiral sequence . To summThis sequence does not include any black blood pulses  as this would have disrupted the continuous acquisition of data necessary for calculation of the respiratory navigator and retrospective cardiac gating. No off-resonance correction was performed as this would have increased the scan time or reduced the temporal resolution of the scan. Some minor image blurring was observed around fat tissue, but this did not severely affect the velocity measurements as the fat was generally spatially separated from the myocardium. Background phase offsets were minimized in the TPM data by optimizing the flow gradients and correcting for Maxwell terms. This resulted in no observable background phase offsets in the data.rad), tangential (Vtang) and longitudinal (Vlong) velocities [All images were processed using an in-house plug-in for OsiriX . For eaclocities . For eacSTATA 13 was used for statistical analyses. Data were examined for normality using the Shapiro-Wilk test. Descriptive statistics are expressed as mean ± standard deviation (SD) when normally distributed and median  when non-normally distributed. Proportions are expressed as percentages.n = 11). The Mann–Whitney-U test was used for non-parametric data (n = 9). Fisher’s exact test was used to compare proportions data (n = 3). For subgroup analysis, PH patients were divided into 3 groups: PH associated with connective tissue disease (CTD), PH not associated with CTD, and chronic thromboembolic PH (CTEPH). The Kruskal-Wallis test was used to test for equality of abnormal global myocardial velocities (n = 5) between the different sub-groups of PH. The group of tests comparing normal controls to patients was considered a single family of statistical inferences and the familywise error rate was controlled using Bonferroni correction. Specifically, we adjusted for 28 statistical comparator tests resulting in a corrected critical p-value of <0.0018.Independent samples t-tests with Welch’s correction for unequal variances were used to compare parametric data in PH patients and controls . In addition, this analysis was used to assess the timing of the Erad peak, which on visual inspection appeared to vary between segments. Bonferroni correction was required to control the familywise error rate in this group of 6 generalized least squares models, and the adjusted critical p-value was 0.0083.Random-effects generalized least squares models were used to compare myocardial velocities in the four myocardial segments. Interaction terms for the myocardial segment and presence of disease were included in the models. This analysis was only performed if the global velocities were abnormal . The decision to list a patient for transplantation or commence intravenous vasodilator therapy was based upon clinical assessment of deterioration in functional class and/or cardiac catheterization derived hemodynamic data. CMR data were not used in these management decisions and the physicians involved in the patients’ care were blinded to the CMR results. Univariate Cox proportional hazards analysis was used to assess the predictive ability of all CMR variables in the 34 patients without proximal CTEPH and not treated with intravenous epoprostenol. The primary outcome was freedom from death, transplantation or progression to intravenous therapy. The E and S waves and conventional CMR metrics with the greatest hazard ratios were entered into a multivariable Cox proportional hazards analysis to determine which covariates were independent predictors of clinical worsening. A p = 0.30). Thirty-out-of-forty patients were female compared to 16 out of 20 controls (p = 0.76). Patient characteristics and underlying diagnoses are detailed in Table There was no difference in the age distribution of PH patients and normal controls (50 years (IQR: 45–59 years) versus 47 years (IQR: 42–54 years) respectively, Conventional CMR metrics from normal subjects and PH patients are shown in Table 5 (IQR 402–717 dyn · s/cm5) and average mPAP was 46 ± 13 mmHg. All patients had a PCWP < 15 mmHg.Median 6-MWD in PH patients was 372 m (IQR: 286–450 m). Twenty-nine PH patients underwent clinically indicated right heart catheterization within 40 days of CMR . Median pulmonary vascular resistance (PVR) was 523 dyn · s/cmMyocardial velocities were acquired successfully in all subjects. Figure rad, Elong and S2tang velocities, with reversal and significant change in both Etang peaks. This can be appreciated in Fig. tang waves was highly discriminatory for the presence of PH. All patients had a reversed E1tang compared to 4/20 normal subjects (p < 0.0001), while 32/40 patients had a reversed E2tang compared to 2/20 normal subjects (p < 0.0001). The magnitude of all abnormal global myocardial velocity peaks did not differ between etiological groups (p > 0.59).Global myocardial peak velocities in normal subjects and PH patients are summarized in Table rad velocity peaking in the anterior segment first  as seen in Fig. rad peaks (p > 0.07).Figure long peak velocity was similar in the inferior wall and septum (p = 0.88) but higher in the anterior (p = 0.008) and lateral walls (p < 0.001). However, in patients, this regional variation was less distinct .Longitudinal velocity maps are shown in Fig. nct Fig.  with onlFigure rad and Elong strongly correlated with mPAP, RVESV and E/A ratio. In addition, peak Erad also correlated with LVSV. The first global Etang peak only correlated with RVESV . The second Etang and Stang peaks did not correlate with any of the tested metrics (p > 0.1). In a generalized least squares model that included mPAP, RVESV, LVSV and E/A, only RVESV was independently predictive of either longitudinal or radial E wave velocities .Univariate hemodynamic correlates with abnormal global myocardial velocities are shown in Table rad peak . The strongest S wave myocardial velocity was the lateral Srad peak . The conventional RV metric with the strongest correlation to 6-MWD was RVEF  and the strongest conventional LV metric was LVSV . In addition, there was a significant correlation between 6-MWD and E/A ratio . When these metrics were inputted into a multiple linear regression analysis, only global Erad  and lateral Srad  were independent predictors of 6-MWD.All correlates with 6-MWD are shown in Additional file All five patients who had operable proximal CTEPH underwent subsequent thromboendarterectomy, and one PAH patient was already receiving intravenous vasodilator therapy at the time of CMR study. Clinical worsening was studied in the remaining 34 patients. Over a median follow-up period of 20 months (IQR 7.9 months), 8 patients were started on intravenous therapy and 1 died.long peak (6.3× increase in hazard per SD reduction in the magnitude of the peak velocity). The strongest conventional RV metric was RVEF (2.4× increase in hazard per SD reduction in RVEF). In addition, septal curvature was also predictive of clinical worsening (3.6× increase in hazard per SD distortion of septum towards the LV). Conventional LV metrics and E/A ratio did not predict clinical worsening. When global Elong peak, RVEF and SC were inputted into a multivariable cox regression model, only global Elong was an independent predictor of clinical worsening (p = 0.009).Metrics that predicted clinical worsening on univariate cox regression analysis are shown in Additional file rad and Elong velocities, and reversal of both Etang waves; ii) Peak global Erad velocity was an independent predictor of 6-MWD; and iii) Peak global Elong velocity was an independent predictor of clinical worsening. These results demonstrate that LV myocardial mechanics are negatively affected by RV pressure overload and may contribute to symptoms and clinical worsening.This is the first study to use TPM to assess LV myocardial velocities in patients with PH. The main findings were: i) Patients with PH had reduced global Erad peak, further corroborating our hypothesis. The exact mechanism underlying the reversal of the Etang peaks is not clear from our results. A possible explanation might be the significant geometric alterations seen in patients with PH, but this requires further study.In keeping with previous studies, our results indicate that PH is primarily associated with early diastolic LV dysfunction , 8, 22. It should be noted that these diastolic abnormalities could be the result of LV remodeling and intrinsic myocardial stiffening. This is particularly pertinent in our patient population due to the high prevalence of CTD, which is known to cause diastolic dysfunction . Howeverrad was an independent predictor of 6-MWD in a model adjusted for resting LVSV. This suggests that resting Erad may be a better predictor of exercise stroke volume augmentation than resting LVSV. In addition, the lateral Srad peak was also predictive of 6-MWD. This is interesting because the population Srad peaks were similar in patients and controls. Nevertheless, patients did have greater variance in Srad, which may explain the exercise findings. The increased peak systolic velocity seen in some patients is probably an attempt to maintain cardiac output in the face of worsening disease. Conversely, the reduced peak velocity found in other patients is possibly due to intrinsic LV systolic dysfunction or abnormal septal interactions.We have shown that lower radial and longitudinal E wave velocities are associated with reduced 6-MWD. This is in keeping with E wave velocities being a marker for diastolic dysfunction, which is known to limit augmentation of stroke volume during exercise. In keeping with the pivotal role of stroke volume, it is unsurprising that resting LVSV also correlated with 6-MWD. However, global Elong, predicted clinical worsening. This is probably because patients with impaired diastolic function have less cardiac reserve and are therefore more symptomatic. This increases the likelihood of up-titration of therapy or death. The reasons why longitudinal rather than radial E wave is a better predictor of progression are not obvious from our data. One possibility is that longitudinal velocities might integrate more measures of cardiac dysfunction than simply reduced LV filling. Importantly, E/A ratio was similar in patients and controls and did not independently predict 6-MWD or clinical worsening. This demonstrates the benefits of TPM over conventional measures of diastolic dysfunction.We also found that E wave velocities, in particular global Erad, nor was it an independent predictor of clinical worsening in a model adjusted for global Elong. These results suggest that reduced LV diastolic function may be more important than RV function itself. This is consistent with studies in patients with other forms of RV pressure overload. For instance, in congenital heart disease it has been shown that improved exercise capacity after relief of RV outflow obstruction is primarily due to better LV filling [In keeping with previous studies, RVEF did correlate with 6-MWD and predicted clinical worsening . However filling .We used TPM to assess myocardial mechanics. However, other CMR methods of assessing myocardial motion do exist. These include tagging, strain encoding (SENC) and displacement encoding with stimulated echoes (DENSE) . AlthougOur feasibility study represents a single center experience of applying TPM to a small patient cohort. Furthermore, the low mortality in this population required a more broadly defined composite outcome measure that included transplant and intravenous therapy. Unfortunately, such ‘soft’ outcome measures are more susceptible to bias . In addition, the population was heterogeneous with a high number of patients with CTD, possibly limiting the applicability of the results to the majority of PH patients. Therefore, this can only be considered a feasibility study demonstrating that TPM data may be of clinical interest in this group of patients. Nevertheless, the positive findings do warrant further work in this area.Other limitations include the fact that catheter hemodynamic data was not available in all patients and that formal tissue characterization was not performed. In future studies, it will be vital that these deficiencies are addressed.A final important limitation is that RV TPM metrics were not assessed in this study. It has been shown that it is possible to assess RV TPM metrics using our technique . HoweverNovel TPM by CMR is feasible in PH, permitting accurate quantification of global and regional myocardial velocities. TPM metrics of LV diastolic dysfunction in PH reliably discriminate between health and disease, and are also strongly predictive of functional capacity. TPM may also be incrementally beneficial in identifying clinical worsening in PH compared with conventional CMR metrics of RV function. These feasibility data support the application of the technique to a larger group of patients over a longer follow-up period. This would allow full determination of the prognostic capacity of LV TPM metrics in PH. Future work should also be directed at assessing the response of these novel biomarkers to vasodilator therapy.


Purpose: Blocks have been used to protect heart from potential radiation damage in left-sided breast treatments. Since cardiac motion pattern may not be fully captured on conventional 3DCT or 4DCT simulation scans, this study was intended to investigate the optimization of the heart block design taking the cardiac motion into consideration.Materials and Methods: Whole breast treatment plans using two opposed tangential fields were designed based on 4DCT simulation images for 10 left-sided breast cancer patients. Using an OBI system equipped to a Varian Linac, beam-eye viewed fluoroscopy images were acquired for each of the treatment beams after patient treatment setup, and the MLC heart blocks were overlaid onto the fluoroscopy images with an in-house software package. A non-rigid image registration and tracking algorithm was utilized to track the cardiac motion on the fluoroscopy images with minimal manual delineation for initialization, and the tracked cardiac motion information was used to optimize the heart block design to minimize the radiation damage to heart while avoiding the over-shielding that may lead to underdosing certain breast tissues.Results: Twenty-three sets of fluoroscopy images were acquired on 23 different days of treatment for the 10 patients. As expected, heart moved under the influences of both respiratory and cardiac motion. It was observed that for 16 out of the 23 treatments, heart moved beyond the planed heart block into treatment fields and MLC had to be adjusted to fully block heart. The adjustment was made for all but one patient. The number of the adjusted MLC leaves ranged from 1 to 16 (mean = 10), and the MLC leaf position adjustment ranged from 2 to 10 mm (mean = 6 mm). The added heart block areas ranged from 3 to 1230 mm2 (mean = 331 mm2).Conclusion: In left-sided whole breast radiation treatments, simulation CT (and 4DCT) based heart block design may not provide adequate heart protection for all the treatments. A fluoroscopy-based method has been developed to adaptively optimize the heart MLC block to achieve optimal heart protection. Radiotherapy is an effective treatment modality for early-stage breast cancer –7. HowevTo minimize the potential cardiac toxicities from breast cancer radiation treatments, various breath control techniques were investigated for their control of the heart doses received in the breast radiation treatments –19. The Heart blocks are usually designed based on the heart shapes outlined on the simulation CT images or directly on the beam’s eye views of digitally reconstructed radiographs/regular radiographs of the radiation. However, since heart constantly moves, the heart outlines captured on the conventional CT images and radiographs may not reflect the full ranges of the motion. Although 4DCT may be used to analyze and incorporate the motion in the block design, it is often too slow to accurately estimate the heart motion. Furthermore, the heart block inevitably shields some breast tissues, which may require to be irradiated, from radiation, leading to potential target miss. The question remains on how to optimize a balance between minimal target miss and maximal heart block while incorporating heart beating motion. This study is to utilize an in-house developed fluoroscopy image rendering and registration algorithm to evaluate and optimize the heart block during left-sided whole breast irradiation treatments. The project was conducted under an IRB approved protocol.For left-sided breast cancer radiation treatments that require heart blocks, due to the nature of potential heart movement, the fluoroscopy imaging modality of the On-Board-Imaging (OBI) system equipped to linear accelerators can be used to dynamically check the appropriateness of the heart block designs at treatment. Ten patients were randomly selected from a pool of left-sided breast cancer patients who would receive the whole breast irradiation and required heart blocks. The whole breast treatments, using two opposed tangential fields, were planned based on 4DCT simulation images. In the plans, the heart blocks were manually designed and shaped with MLCs . The heart block designs took the considerations of heart locations on the 4DCT and clinical evaluation of the blocked breast tissues. For the 10 patients included in this study, the heart blocks were all such designed so that the block edges covered the heart borders reflected on the 4DCT average image sets.Using an OBI system equipped to a Varian Linac, beam-eye viewed fluoroscopy images (for a duration of 10–15 s) were acquired for each of the treatment beams after patient treatment setup, and the MLC heart blocks were overlaid onto the fluoroscopy images with an in-house software package. A non-rigid image registration and tracking algorithm was utilized to track the cardiac motion on the fluoroscopy images with minimal delineation for initialization, and the tracked cardiac motion information was used to optimize the heart block design to minimize the radiation damage to heart while avoiding the over-shielding that may lead to underdosing certain breast tissues. To be consistent with the principle of heart block design in plans, the fluoroscopy-based heart block optimization was achieved when the MLC edges were adjusted to cover the heart borders imaged on the fluoroscopy.A brief description of the non-rigid image registration and tracking algorithm as well as the MLC shape optimization principle is presented as follows.Patient heart was initially delineated in fluoroscopy using the combination of CT to fluoroscopy image registration and was manually adjusted on the first frame of the fluoroscopy. The heart motion was then dynamically tracked in fluoroscopy using the registration propagation algorithm as briefly described below.C, the registration between two fluoroscopy frames is based on an enhanced Demons algorithm, which uses the following equation of active force at point i ∈ C:m is the moving (target) frame, s is the static (source) frame, and a is a weighting parameter that controls the step size in the deformation. A constraint is defined as another force term jf is the image force at a neighboring point j on the heart contour, and σ is the size of the neighborhood in which the smoothness factor will be effective.Given the initial heart delineation cλ and dλ are weights for the image force and the object constraint, respectively. We use empirical values that cλ = 0.25 and dλ = 0.75 for the calculation of the overall deformation force in the registration since these two values performed the best.The accumulative force driving the deformation can be expressed as:xd, yd, zd,) between corresponding pixels in different frames is calculated to generate a motion model so that the displacement at any point i in the heart contour on any two neighboring fluoroscopy frames can be expressed as:j + 1 and j, respectively. To retrieve the heart motion throughout the fluoroscopy, we propagate the registration to get the motion between any two arbitrary fluoroscopy frames j and k using:To improve the efficiency, the registration is conducted for cropped regions only. The size of the cropped region is automatically determined based on the delineation of the heart surface. Hierarchy strategy and frequency domain calculation are used to further speed up the registration process. After the registration, the motion vector  treatment planning system as the MLC file and loaded into our internally developed software. After the retrieval of heart motion, the maximal offset between the heart motion inside the treatment beam and the corresponding MLC leaf position is computed and used to adjust the MLC position in the original treatment plan to maintain full heart shielding.In the heart block MLC position optimization process, if heart was adequately covered by the planned MLC positions, no MLC position adjustment was made; if it was found that heart was not adequately covered by the planned MLC, the MLC positions were adjusted so that the MLC edges covered the most infiltrating borders of heart into the corresponding field of radiation detected on the fluoroscopy images.The optimized MLC heart blocks were checked for their appropriateness by an experienced radiation oncologist.2 (mean = 331 mm2). The results are summarized in Table For the 10 patients, 23 sets of fluoroscopy images were acquired on 23 different days of treatment , in terms of motion frequency and magnitude, is very likely not exactly reproducible. The revised heart blocks, based on the fluoroscopy images acquired prior to the treatment, may not provide complete heart protection during the radiation beam-on time, if the organs do not exhibit the motion patterns as imaged on the fluoroscopy.2. Given that typical tangential breast field size is over 20,000 mm2, it is reasonable to assume that for most cases, the heart block adjustment at treatment will have insignificant impact to the dose distributions with same machine outputs. However, in certain extreme cases, the block area change could be as large as over 1200 mm2  based heart block design may not provide adequate heart protection for all the fractions in left-sided whole breast radiation treatments. A fluoroscopy-based method has been developed to adaptively optimize the heart MLC block to achieve optimal heart protection. On the other hand, additional study needs to be conducted to seek an optimal balance between protection of heart and assurance of entire breast tissue irradiation.This project was presented as an oral presentation at the 55th annual AAPM meeting in August 2013, Indianapolis, IN, USA.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Two-dimensional longitudinal strain (LS) is a quantitative and automated technique for the measurement of global long-axis function in any cardiac chamber. Observational studies of left ventricular function in adults suggest that global LS correlate with EF, and is superior to EF as a predictor of outcome. Global LS can be derived by cardiac magnetic resonance (CMR), however its application in routine clinical practice is hampered by the lack of chamber-specific normative data. The purpose of this investigation is to provide reference data for atrial and ventricular global LS during childhood and adolescence by CMR feature tracking (FT).We prospectively enrolled healthy children and adolescents in participating centers of the German Competence Network for Congenital Heart Defects. CMR was performed on 1.5T scanners and consisted of a stack of standard two-dimensional steady-state free-precession (SSFP) acquisition covering the whole heart in the transverse plane. CMR-FT was performed on ventricular horizontal long axis SSFP images  for derivation of right and left atrial , and right and left ventricular  peak global LS . Atrial and ventricular ejection fractions (EF) and end diastolic volumes (EDV) were also measured . Correlations were explored for LS with age, body surface area (BSA), gender, and EDV and EF of each chamber.2). The mean ± SD of LS (%) for RA, RV, LA and LV were 26.6±10, 18±5, 26.5±10.6 and 17.5±5 respectively. There was significant positive correlation of LS in the LA, LV, RA and RV with corresponding EF . Gender-wise differences  were not significant for atrial and ventricular LS, and correlations with age and body surface area were generally weak. Inter and intra-observer comparisons in 20 randomly selected subjects showed good agreements for both atrial and ventricular LS.There were 115 subjects (male: female 56:59, mean age 12.4 ± 4.1 years; range, 4.4-20.3 years, BSA 1.4±0.4 mThis investigation provides chamber-specific nomograms for pediatric atrial and ventricular LS to serve as clinical reference, and to facilitate future CMR-based deformation research.German Competence Network for Congenital Heart Defects.


Background: Physical activity (PA) can support cancer patients during medical treatment by reducing side-effects and increasing quality of life. However, PA levels mostly decline after diagnosis. Which factors can explain if patients are able to remain or even increase their PA level? Self-efficacy is an important cognitive factor that has been linked to cancer patients' PA across many studies. In contrast, affective factors such as PA enjoyment have rarely been examined. We compare the influence of self-efficacy and PA enjoyment on cancer patients' PA levels after completion of an exercise or stress-management intervention.Methods: Outpatient cancer patients  were enrolled in the MOTIVACTION study, a 4-week intervention , with pre-test (T1), post-test (T2), and a 10-week follow-up (T3). Participants were randomized to either an exercise intervention (emphasizing self-regulatory strategies for behavior change) or to a stress management intervention (coping and relaxation techniques). Sixty-seven patients remained in the study and completed the SQUASH assessment of PA, a measure of maintenance self-efficacy  and PA enjoyment . Regression analyses were calculated with PA level (at T2 and T3) as dependent variable and relative weight analyses were conducted. The study was registered at clinicalTrials.gov .Results: Baseline self-efficacy and change in PA enjoyment significantly predicted cancer patients' PA level at T2 adjusting for baseline PA and type of intervention. Relative weight (RW) analysis revealed that PA enjoyment (baseline and change together) explained 34.3% of the dependent variable, self-efficacy (baseline and change) explained 38.4%. At follow-up, self-efficacy was still a significant predictor of PA (RW = 74.6%), whereas PA enjoyment was no longer a relevant factor (RW = 5.2%).Conclusion: The affective factor PA enjoyment was equally important as self-efficacy for predicting cancer patient' PA level directly after completion of the intervention. Reasons for the reduced relevance at follow-up and a broader range of affective factors should be analyzed in future studies on cancer patients' PA level. Regular physical activity (PA) has various beneficial effects for cancer patients both during and after medical treatment  between perceived behavioral control (similar to self-efficacy) and PA level/ intention in a cross-sectional study of 600 colorectal cancer survivors , perceived barriers (r = −0.27), and PA enjoyment (r = 0.41) were the strongest correlates of PA , which investigated the relative importance and interrelationships between self-efficacy and PA enjoyment in predicting the initiation and maintenance of PA  over and above the cognitive variable self-efficacy (research question 1). Furthermore, we were interested to explore whether self-efficacy and PA enjoyment increased during the interventions (research question 2). Finally, additional analysis examine exploratively which factors are associated with changes in PA enjoyment.https://clinicaltrials.gov/ct2/show/NCT01576107?term=motivaction&rank=1).The MOTIVACTION  study consisted of two interventions (exercise and stress management) and assessments at baseline (T1), 4 weeks after the intervention (T2), and 10 weeks after T2 (T3). Patients were randomized to one of the two groups by being stratified by sex, age , metastases , and current chemotherapy . The study protocol was approved by the ethic committee of the medical faculty in Heidelberg, Germany. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The study was registered at clinicalTrials.gov  or finished this therapy not longer than 6 months ago, being ≥ 18 years, being below the current guidelines to be moderate active at least for 150 min per week, and being able to follow the study instructions. Exclusion criteria were: planned rehabilitation or inpatient treatment during the next 8 weeks, wound healing not completed, bone metastases, and serious comorbidities or comorbidity-related limitations.Participants were recruited at the National Center for Tumor Diseases in Heidelberg (Germany). In an initial (telephonic) meeting participants were screened if inclusion or exclusion criteria apply. Among others, patients were asked to rate their PA behavior in minutes during the last week. If the patients were less active than 150/min per week they were categorized as insufficiently active and could be enrolled in the study (if no other exclusion criteria occurred). After signing written informed consent participants were randomized either into the exercise or stress management group and received the baseline questionnaires. Both the exercise as well as the stress management intervention started immediately after returning baseline materials and consisted of an individual 1-h-counseling session, followed by three weekly telephone calls.The exercise intervention included counseling based on the Health Action Process Approach  having good psychometric properties . As the intervention focused on exercise behavior and not PA in general, we generated the variable “intended physical activity level” (iPAL). We classified the activities according to Caspersen et al.  as exerct-tests for metric and Chi-squared tests for nominal variables. The first research question was analyzed using linear regression models and relative weight analysis. Relative weight analysis estimates the relative importance of correlated determinants in a regression equation by using a new set of uncorrelated determinants that are maximally related to the original set of correlated determinants . Descriptive statistics and bivariate Pearson correlations were conducted. Drop-out analyses were calculated to compare completers versus non-completers of the intervention using p < 0.05.Listwise deletion was used if necessary in all analyses, as there were only less than 2% of data missing. Analyses were carried out with IBM SPSS Statistics 22 IBM corp. NY, USA, and employed a significance level of M = 47.22 min). They were randomized to the exercise intervention (n = 36) or to the stress management group (n = 36), with 67 completing the study . The majority had breast (33%), colorectal (12%), or prostate cancer (8%) with 33% having metastases and 37% having currently chemo-therapy  at baseline. Mean values of iPAL , PA enjoyment , and self-efficacy  did not differ significantly between the exercise intervention and the stress-management group before the start of the intervention (T1) (p > 0.05).Descriptive results and bivariate correlations are shown in Tables MT1 = 52.14, SDT1 = 101.95; MT2 = 150.43, SDT2 = 161.13; MT3 = 189.43, SDT3 = 243.14; stress-management group: MT1 = 41.84, SDT1 = 92.47; MT2 = 69.06, SDT2 = 121.10; MT3 = 120.00, SDT3 = 193.38). The first hierarchical regression analysis predicting iPAL at T2 could explain 22.8% of variance in the first step  and further 5% in the second step . Self-efficacy (at T1 and ΔT2T1-) was a positive significant predictor, and ΔT2T1-PA enjoyment could predict iPAL at T2 over and above this cognitive influence (β = 0.32). Relative weight analysis revealed that self-efficacy and PA enjoyment were of about equal importance in predicting iPAL at T2  16.4% of variance could be explained and only self-efficacy at T1 had a significant effect . In the second step, PA enjoyment (at T1 as well as ΔT2T1-) did not add any variance and was no significant predictor  = 7.317, p = 0.001] and also marginally self-efficacy  increased across the three measurement points  = 0.029, p = 0.866, Finteraction = 0.040, p = 0.961; self-efficacy: Fcondition = 0.012, p = 0.915, Finteraction = 0.150, p = 0.860]. Thus, the factor type of intervention was left out in an additional analysis yielding very similar results . Post-hoc analyses revealed that the significant increase in PA enjoyment and marginally in self-efficacy only took place between T1 und T2 , thus during the intervention. The difference to baseline remained significant at T3 .Two ANOVAS with repeated measures showed that both PA enjoyment  were included in a regression analysis as independent variables (dependent variable = ΔT2T1-PA enjoyment). The regression analysis could explain 37% of the variance in the change of PA enjoyment. Low PA enjoyment at T1 , a high increase in iPAL between T1 and T2  and a younger age  were significant predictors of an increase in PA enjoyment.To examine factors being associated with the significant increase in PA enjoyment (between T1 and T2) at first bivariate correlations were regarded (see Table Increasing evidence hints to the important role of affective factors in the process of behavior change (see introduction). Positive affects might be especially important in an oncological setting, as a cancer diagnosis and oncological treatment is linked to emotional distress and negative emotions  predicted the iPAL of cancer patients directly after the intervention. A relative weight analysis showed that the effect of PA enjoyment was comparable in its size to the one of the well-established cognitive factor self-efficacy. This is in line with previous studies showing the prominent role of PA enjoyment in predicting PA behavior in healthy adults , surprisingly, PA enjoyment did not have any influence on iPAL at the 10-week follow up (T3). This is in contrast to findings of Lewis et al. , who comIf results of our study and the one by Rogers et al.  can be rvicarious experience and personal persuasion) or physical arousal during exercising (similar to the last source of self-efficacy) might be relevant as well and should be examined in future research. Moreover, the characteristics being a younger patient and having low scores on PA enjoyment should be prescreened in future studies and in current counseling initiatives to define the most valuable group for PA behavior change  in cancer patients. Furthermore, within these patient groups the value of affective exercise components like competition-orientated tasks should be integrated in future study designs.Results of our study furthermore showed an increase in PA enjoyment and also marginally in self-efficacy during a 4-week behavior change intervention (in an exercise intervention as well as in a stress management group). The increase in self-efficacy is in line with Banduras theory Bandura, , 2000, pOur study has several limitations. Firstly, PA enjoyment has been measured with two items only. Although it has a good internal consistency and is based on a measure used in other oncological studies  could be compared to a theory focusing on affective factors. One of the rare affective theories called “affect and health behavior framework” was proposed by Williams and Evans . This coIn conclusion, our study was the first study examining the relative importance of PA enjoyment in comparison to the classical cognitive factor self-efficacy in a PA promotion intervention for cancer patients. At least in the short term affective factors such as PA enjoyment seem to play an important role for cancer patients to increase their PA level.NU contributed substantially to the conception and design of the work, performed statistical analyses and drafted the manuscript. JW supervised and supported the conception, design and implementation of the study and revised the work critically. MS supervised and supported the conception and design of the study, interpreted the data of the work and revised the work critically. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To test the validity of diffusion tensor imaging (DTI) measures of tissue injury by examining such measures in a white matter structure with well-defined function, the medial longitudinal fasciculus (MLF). Injury to the MLF underlies internuclear ophthalmoparesis (INO).40 MS patients with chronic INO and 15 healthy controls were examined under an IRB-approved protocol. Tissue integrity of the MLF was characterized by DTI parameters: longitudinal diffusivity (LD), transverse diffusivity (TD), mean diffusivity (MD) and fractional anisotropy (FA). Severity of INO was quantified by infrared oculography to measure versional disconjugacy index (VDI).LD was significantly lower in patients than in controls in the medulla-pons region of the MLF (p < 0.03). FA was also lower in patients in the same region (p < 0.0004). LD of the medulla-pons region correlated with VDI  as did FA in the midbrain section .This study demonstrates that DTI measures of brain tissue injury can detect injury to a functionally relevant white matter pathway, and that such measures correlate with clinically accepted evaluation indices for INO. The results validate DTI as a useful imaging measure of tissue integrity. Conventional imaging of the central nervous system (CNS) is well-established for diagnosis of multiple sclerosis (MS) and for testing disease-modifying agents in clinical trials. However, MS lesions that appear similar on conventional imaging display wide heterogeneity on histopathology, with varying degrees of astrogliosis, demyelination and remyelination.Advanced imaging methods such as diffusion tensor imaging (DTI) offer quThe MLF is a pair of white matter pathways that carries neural signals essential to conjugate eye movements. The MLF connects the paramedian pontine reticular formation (PPRF) and abducens nucleus to the contralateral medial rectus subnucleus of cranial nerve III. When phyThe most common consequence of lesions in the MLF is internuclear ophthalmoparesis (INO). INO is characterized by slowing of the adducting eye on the side of the MLF lesion and is bInfrared oculography quantifies the severity of INO to high precision.,5 One meDifficulty in validation of quantitative imaging results as much from properties of commonly-used scales of functional disability as from the imaging. Commonly-used scales of functional disability such as the EDSS and MSFC are inherently coarse. The precision and sensitivity infrared oculography yield a continuous range of VDI that better matches the quantitative measures provided by DTI.Furthermore, the functional disability measured by infrared oculography tightly associates with injury to a well-defined neural pathway, the MLF. In contrast, the EDSS and MSFC characterize complex functions, such as walking, that involve neural circuits that are widely distributed and heterogeneous.DTI provides quantitative measures of tissue injury that refThe institutional review board at University of Texas Southwestern Medical Center reviewed and granted approval for this study. After obtaining written consent, 40 MS patients with chronic INO were examined  and 15 healthy controls . Chronic INO was defined as the absence of an episode of diplopia in the past year. All patients had pontine MLF involvement visualized on T2-weighted images. Each subject underwent infrared eye movement evaluation as previously described[Eye movement disconjugacy measurements were performed by infrared oculography. Differences between left and right eye during left-directed and right-directed 20 degree saccades were characterized using left (left eye abduction velocity divided by right eye adduction velocity) and right (right eye abduction velocity divided by left eye adduction velocity) versional disconjugacy index (L-VDI and R-VDI). Large va2 and 1 b = 0 volume, NEX = 2, TE = 66 msec, TR = 20 heartbeats). Cardiac triggering used a fingertip plethysmograph to acquire one slice per heartbeat at a delay of 300 msec after the peak of the pulse. Image slices were aligned perpendicular to the posterior edge of the pons and covered the pons. For coregistration purposes, a whole-brain b = 0 image with same angulation as the high spatial resolution DTI was also acquired . Images were subject to iterative motion correction[All MR imaging was performed at a whole-body 3T scanner using an 8-channel head coil . Imaging featured high spatial resolution DTI with physiological triggering to minimize pulsatile artifacts , axial thin-slice T2-weighted images located at the pons , sagittal T1 MPRAGE , and axial phase maps .th generation symmetric Average Brain Stereotaxic Registration Model)[The MLF was localized using an atlas-based method. Regions of interest (ROI) corresponding to the left and right MLF were drawn by a neurologist with expertise in brainstem neuroanatomy (EF) on the MNI atlas  providedon Model) Fig 1)..th generon Model) and a bron Model) Transforon Model),18 BecauDTI of the MLF differentiates MS from controls in certain sections of brainstem. T2 lesions overlapped the MLF ROI in 33 of the 40 patients. The lesions were in the medulla-pons region (-39 ≤ z ≤-32) in 11 patients, in the midbrain region (-21 ≤ z ≤ -18) in 5 patients and in both regions in 1 patient. To assess the impact of T2 lesions on DTI measures, values within and outside T2 lesions were compared. For each patient and for each region (medulla-pons or midbrain), the MLF ROI was split into two parts—within the T2 lesion and outside the T2 lesion—and paired by patient. The mean value of each DTI measure  was taken in each part. A paired t-test comparing within- and outside-lesion DTI measures found no significant differences (p > 0.7). Data from the patient without a T2 lesion was excluded from the analysis. If a T2 lesion did not reside in a region for a given patient, data was not included in the comparison.The work presented here demonstrates that injury to a specific brainstem pathway, the MLF, can be detected by DTI. DTI measures of tissue integrity also correlate with quantitative measures of functional impairment. This further expands the findings of our previous pilot study using a smaller cohort and 1.5T imaging.LD is often interpreted as a marker of axonal integrity. Reduced As MS is a demyelinating disease, we expected TD, often considered a marker for demyelination, to be higher in MS patients than in controls. However, we did not observe a difference in TD between MS and controls. The most straightforward interpretation of this result is that the imaging approach does not have sufficient sensitivity to demyelination in this region. Higher signal to noise ratio, larger sample size or different approaches to quantifying myelin density, such as magnetization transfer, may be required to quantify demyelination in the MLF.−5). After the acute stage of lesion formation, LD is typically increased in MS patients, but these observations are not performed in the brainstem. There is increasing recognition that the interpretation of DTI indices in terms of injury, such as demyelination and axonal transection, is incomplete. For example, low FA is typically interpreted as an indicator of tissue injury, but elevated FA has been associated with injury due to Alzheimer’s disease [The observation that LD is higher among MS patients than in controls in the midbrain region (-21 ≤ z ≤ -18) is harder to interpret. Elevated diffusivity can be an artifact associated with partial volume averaging with nearby cerebrospinal fluid. However, ROIs were placed to avoid overlap with CSF spaces and corrections were used to account for partial volume averaging. Furtherm disease ,23. The  disease  may be nMeasuring DTI characteristics of the MLF is challenging. In principle the MLF may be identified by deterministic or probabilistic tractography, but our previous studies found that the small diameter of the MLF  and the presence of large, parallel pathways make such approaches inconsistent and unreliable. We thereMean values of LD, TD, MD and FA were taken at each slice level of each ROI in each subject. An alternative approach would be to include values for all voxels without taking the mean. Including all voxels in the analysis is feasible but introduces complexity. The transformation of the ROI from the MNI template to each subject’s image coordinates does not preserve the number of voxels at each slice level. Therefore, the number of voxels would have to be included as a covariate in the analysis. Due to the limitations of the statistical power of the measurement, a number of questions remain unanswered. Right and left MLF were not considered separately. It would be interesting to determine the extent to which the observed changes in DTI are due to tissue in lesions as opposed to normal appearing white matter. A clean test would include additional patients who do not have lesion involvement in the MLF—a cohort not included in this study. With a more extensive study, it may be possible to investigate differences between subtypes of INO, such as anterior vs. posterior or unilateral vs. bilateral.This study is a step toward validation of quantitative measures from advanced imaging in a patient-specific model. This study demonstrates that DTI can detect injury to a small brainstem pathway, the MLF. Furthermore, DTI measures of injury correlate with a precise and sensitive measure of functional disability, infrared oculography, in the presence of INO. Studies focusing on neural systems with well-defined function provide a patient-relevant approach for testing quantitative imaging.


Left ventricular thrombus (LVT) formation occasionally complicates patient recovery post myocardial infarction, conveying a significant risk of systemic embolism. Accordingly, thrombus detection and subsequent anticoagulation is imperative in order to minimize patient morbidity and mortality. Transthoracic echocardiography (TTE) is the imaging modality most widely used to screen for thrombus formation despite its suboptimal sensitivity and specificity.This report describes the discordant imaging findings of a LVT in a 56 year old Caucasian male with an anterior ST elevation myocardial infarction. Left ventriculography revealed a filling defect, suggestive of a potential left ventricular (LV) thrombus, which could not be confirmed by TTE. Cardiac magnetic resonance imaging (MRI) demonstrated evidence of a full thickness scar involving the mid to distal anterior wall and apical regions, with confirmation of a small LV apical thrombus.This case illustrates the limitations of TTE when used as a tool to screen for thrombus formation. It highlights the importance of multimodality cardiac imaging for the detection of post myocardial infarction (MI) complications, in the context of a high clinical suspicion. Left ventricular thrombus (LVT) formation constitutes a significant concern for patients post myocardial infarction (MI). Approximately 4% of ST elevation myocardial infarction (STEMI) patients treated aggressively with primary percutaneous intervention (PCI) therapy demonstrate evidence of a LVT by contrast echocardiography . The majThe significance of LV thrombi stems not only from its epidemiology but also its associated morbidity and mortality; a LVT often accompanies larger infarcts and conveys the risk of systemic embolism ,3. Thus,A 56 year old Caucasian male with an anterior STEMI underwent PCI of the left anterior descending artery with a drug eluting stent. Left ventriculography revealed a filling defect within the inferoapical region suggestive of a potential LV thrombus Figure . SubsequThis case illustrates the importance of multimodality imaging in the clinical detection of a LVT when a high degree of suspicion exists. TTE alone was unable to adequately visualize the source of the filling defect demonstrated by left ventriculography. The use of CMR was necessary in this report to confirm the presence of a thrombus, serving to highlight its superior sensitivity and specificity, as well as the limitations of other imaging modalities in thrombus detection.Left ventriculography is a useful imaging modality to screen for LVT in patients undergoing cardiac catheterization post-MI, as was seen in this case. Thrombi appear as discrete filling defects in areas of akinesia or dyskinesia . VentricTTE remains the imaging modality most widely used to screen for LV thrombi, as it is cost effective, accessible, and non-invasive. A LVT appears as an echo-dense mass distinct from the LV wall, but adjacent to an area of abnormal wall motion . DespiteIn contrast to TTE, which identifies a LVT based on anatomic appearance, delayed enhancement CMR (DE-CMR) relies on tissue characterization. The avascular LVT is viewed as an absence of contrast uptake adjacent to hyperenhanced scarred myocardium . DE-CMR The current case illustrates the difficulty associated with LVT detection, as imaging modalities used to screen patients post MI are imperfect. When clinical suspicion is high and imaging results discordant, a third modality should be sought.Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


Surgical correction of tetralogy of Fallot is still one of the most frequently performed intervention in pediatric cardiac surgery, and in many cases, it is far from being a complete and definitive correction. It is rather an excellent palliation that solves the problem of cyanosis, but predisposes the patients to medical and surgical complications during follow-up. The decision-making process regarding the treatment of late sequel is among the most discussed topics in adult congenital cardiology. In post-operative Fallot patients, echocardiography is used as the first method of diagnostic imaging and currently allows both a qualitative observation of the anatomical alterations and a detailed quantification of right ventricular volumes and function, of the right ventricular outflow tract, and of the pulmonary valve and pulmonary arteries. The literature introduced many quantitative echocardiographic criteria useful for the understanding of the pathophysiological mechanisms involving the right ventricle and those have made much more objective any decision-making processes. The complete surgical correction of tetralogy of Fallot (ToF) was first introduced in 1955 , and 2D strain.Indication for bidimensional measures of the RV have been proposed in various guidelines  and origThe complex RV anatomy could be better investigated using three-dimensional echocardiography (3DE). This technology allows better assessment of the pulmonary valve’s morphology , and chaCardiac MRI and echocardiography provide similar information useful for the optimal management of ToF patient. Echocardiography remains as the first-line diagnostic tool. Cardiac MRI is a valid alternative to echocardiography when ultrasound images do not have good resolution and when echocardiography measurements are borderline or ambiguous. Nowadays, echocardiography is superior in estimating gradients and pulmonary arterial pressure and offers optimal assessment of residual RV outflow tract obstruction and residual ventricular septal defect. Cardiac MRI is better than echocardiography for RV volumes and RV EF quantification, evaluation of the RV outflow tract obstruction and pulmonary artery conduits, and for pulmonary regurgitant flow estimation . ObstrucEchocardiographic indicators for studying velocity of displacement and deformation of the myocardium are aimed to a direct quantification of myocardial function not extrapolated from a change of shape and dimension.Tricuspid annular plane systolic excursion (TAPSE) measures the systolic excursion of the RV annular plane toward the apex. It is a very easy echocardiographic measurement, rapid to measure in a busy clinical setting, and is widely used in clinical practice even if its reliability is still controversial , 23. In Tissue Doppler imaging technique measures the velocities of cardiac tissue and has been studied for the assessment of RV function. Tissue Doppler compared to blood flow Doppler reflects directly myocardial function and is less subject to preload changes. However, TDI is still Doppler based, and therefore its major limitation remains the angle dependency . BecauseIsovolumic acceleration time , a suboptimal alignment of the ultrasound beam with pulmonary flow, or in case of pulmonary hypertension and in pulmonary branch stenosis. Pulmonary hypertension and peripheral pulmonary stenosis lead to an underestimation of the severity of the stenosis (reduction of the anterograde peak gradient), and worsens pulmonary regurgitation. Underestimation of pulmonary stenosis should be suspected when the velocity of the tricuspid regurgitation exceeds consistently the velocity of the pulmonary flow. The suspect of pulmonary branch stenosis, which is more common than pulmonary hypertension in operated ToF patients, needs to be ruled out at the time of pulmonary valve replacement.First assessment of pulmonary regurgitation severity should be done with color Doppler: a severe pulmonary regurgitation is recognizable on color Doppler flow as a large retrograde flow that persists beyond the first half of diastole invading the RV outflow tract. After relieve of RV outflow tract obstruction with a transannular patch a severe pulmonary insufficiency appears as a “free floating” bidirectional flow across the pulmonary annulus. To record appropriately the color flow, it is recommended to set the color scale at the maximal pulse repetition frequency available in order to avoid turbulence overestimation. In severe pulmonary regurgitation, the most important determinants of the regurgitant volume are the compliance of the RV and the pulmonary artery, the size of the pulmonary branches, the pulmonary vascular resistance, and its changes throughout the cardiac cycle . QuantifRight ventricle restrictive physiology is a condition observed in congenital heart diseases in which the RV systolic pressure is chronically elevated, and it is mostly encountered in adult patient operated of ToF. A restrictive physiology is typically seen in severely hypertrophied and fibrotic RV with normal sized or only mild ventricular dilatation due to the increasing myocardial stiffness. However, restrictive physiology could also be observed in severely dilated RV. In this case, the restrictive physiology should be intended as a manifestation of poor ventricular compliance that may occur at any stage of the RV remodeling after ToF surgery. Spectral Doppler may be used to identify this condition. Restrictive physiology may limit the degree of pulmonary regurgitation because of an increased mid-to-late diastolic pressure that overrides the pulmonary artery pressure. Therefore, the Doppler curve of the pulmonary regurgitation shows an early peak and an early end regurgitation. This gradient is defined the end-diastolic forward flow (EDFF) and appears just after the atrial contraction Figure Echocardiography is the exam most frequently performed in the follow-up of patients after complete ToF surgical correction. Use of validated echocardiographic indexes based either on conventional echocardiography and newest technologies such as 3DE and 2D strain allows us to integrate the usual subjective observational information with a new set of parameters useful to quantify RV function.However, quantitative criteria represent an advantage when they are objectively repeatable, clinically reliable, and comparable with other quantitative values. This is not yet completely true for some of these echocardiographic indices applied to the RV, but in the near future it is reasonable to expect powerful clinical validation studies and improvements of the technologies in use.Echocardiography with the development of new technologies such as 3DE, 2D strain, and myocardial Doppler imaging has made a great contribution to the follow-up of complex patients affected by congenital heart disease. Notwithstanding that, at present CMRI represents the gold standard for non-invasive quantitative assessment of the RV and should be regularly used in repaired ToF patients especially to evaluate those parameters in which CMRI is considered superior to echocardiography, such as RV volumes and RV EF.The decisions about the complex diagnostic and therapeutic plans have to go through the analysis of all diagnostic techniques applied in these patients, as echocardiography, cardiopulmonary exercise tests, CMRI, CT, hemodynamic studies, electrophysiology, and biochemistry studies.Furthermore, the introduction of more quantitative echocardiographic parameters for the evaluation of the RV has not decreased the number of cardiac catheterizations but it has indeed improved the added value of these invasive procedures probably making more accurate the indications to perform them.The synergy between the information obtained by various methodologies in which the refinement of one technique also improves the level of information obtainable from the others is a further confirmation of the fact that the best diagnostic and therapeutic strategy can be identified only on the base of a multiparametric analysis that correlates data obtained from clinical and instrumental examinations.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Acute myocarditis can be diagnosed on cardiovascular magnetic resonance (CMR) using multiple techniques, including late gadolinium enhancement (LGE) imaging, which requires contrast administration. Native T1-mapping is significantly more sensitive than LGE and conventional T2-weighted (T2W) imaging in detecting myocarditis. The aims of this study were to demonstrate how to display the non-ischemic patterns of injury and to quantify myocardial involvement in acute myocarditis without the need for contrast agents, using topographic T1-maps and incremental T1 thresholds.We studied 60 patients with suspected acute myocarditis (median 3 days from presentation) and 50 controls using CMR (1.5 T), including: (1) dark-blood T2W imaging; >(2) native T1-mapping (ShMOLLI); (3) LGE. Analysis included: (1) global myocardial T2 signal intensity (SI) ratio compared to skeletal muscle; (2) myocardial T1 times; (3) areas of injury by T2W, T1-mapping and LGE.Compared to controls, patients had more edema , higher mean myocardial T1 (1011 ± 64 ms vs. 946 ± 23 ms) and more areas of injury as detected by T2W (median 5% vs. 0%), T1 (median 32% vs. 0.7%) and LGE (median 11% vs. 0%); all p < 0.001. A threshold of T1 > 990 ms  detected significantly larger areas of involvement than T2W and LGE imaging in patients, and additional areas of injury when T2W and LGE were negative. T1-mapping significantly improved the diagnostic confidence in an additional 30% of cases when at least one of the conventional methods  failed to identify any areas of abnormality. Using incremental thresholds, T1-mapping can display the non-ischemic patterns of injury typical of myocarditis.Native T1-mapping can display the typical non-ischemic patterns in acute myocarditis, similar to LGE imaging but without the need for contrast agents. In addition, T1-mapping offers significant incremental diagnostic value, detecting additional areas of myocardial involvement beyond T2W and LGE imaging and identified extra cases when these conventional methods failed to identify abnormalities. In the future, it may be possible to perform gadolinium-free CMR using cine and T1-mapping for tissue characterization and may be particularly useful for patients in whom gadolinium contrast is contraindicated. Acute myocarditis can be detected using cardiovascular magnetic resonance (CMR) using multiple tissue characterization techniques, especially T2-weighted (T2W) imaging for edema and late gadolinium enhancement (LGE) -3. LGE iHowever, there are some limitations in using LGE alone in the diagnosis of acute myocarditis. Very small areas of myocarditis may not always be detected. Some patients demonstrate predominant global edema rather than frank myocyte necrosis, resulting in negative findings on LGE imaging . DiffuseNative (or pre-contrast) T1-mapping directly estimates the T1 (proton spin–lattice) relaxation time of tissues on a pixel-by-pixel basis. Native myocardial T1 values have recently been validated in a large, multicentre normal cohort study to have a tight normal range , and shoIn this study, the hypothesis is two-fold: (1) given that T1-mapping is highly sensitive compared to conventional CMR techniques in detecting changes in myocarditis , we propThis was a prospective study including 60 consecutive patients  presenting with suspected acute myocarditis . PatientCMR studies were performed on a single 1.5 Tesla MR system  using a 32-channel phased-array coil, except for short-tau inversion recovery (STIR) imaging for which the body coil was used, as previously published . Briefly2 above the specified thresholds were considered abnormal [Image analysis of left ventricular ejection fraction was performed using Argus software  on cine images. Analysis of short axis images from T1-mapping, T2W and LGE imaging was performed as previously published ,9. Brief2 maps; 11% of the segments were excluded due to off-resonance artifacts, partial volume effect, poor T1 fit on the R2 maps, patient movement or low SNR; on LGE imaging, 3% were rejected due to artifacts caused by patient movement or poor image quality. To avoid bias towards or against any single technique, main analyses were repeated with all artifacts re-included and results provided in the main text or Additional file Each LV myocardial segment was strictly assessed for image quality before inclusion into the final analyses and only segments with no or minimal artifacts were included, as previously published . On cinet-test, or the Mann–Whitney U test for non-parametric data. Any segmental analysis was averaged on a per-subject basis before any inter-individual and group comparisons to control for clustering of segments within each subject. All statistical tests were two-tailed, with p-values of less than 0.05 considered statistically significant. To determine the presence of significant differences in subject groups when using multiple CMR methodologies, ANOVA analysis was performed with Bonferroni corrected post-hoc comparisons for parametric data; for non-parametric data, the Kruskal-Wallis one-way analysis of variance was performed with post-hoc pairwise comparisons. For comparisons of the extent of myocardial injury measured by multiple CMR methodologies within the same patient subgroup, the Friedman test was used for non-parametric data with post-hoc comparisons. Receiver operator characteristic (ROC) analysis was performed to compare the diagnostic performance of the CMR methods in detecting myocardial changes in patients compared to controls. Significance of ROC analyses was assessed using the method of Delong et al. [Normality of data was tested using the Kolmogorov-Smirnov test. Normally distributed data are presented as mean ± standard deviation (SD); non-parametric data are presented as median with interquartile range (IQR). Unpaired samples between groups were assessed by the unpaired 2-tailed Student’s g et al. . The McNAn example of whole-heart multiparametric tissue characterization is shown in Figure Receiver operator characteristics (ROC) analysis comparing diagnostic performance of the techniques showed that T1-mapping and LGE  were significantly superior to dark-blood T2W imaging in the detection of acute myocarditis . Repeat analysis including all image artifacts showed preservation of all relative relationships and statistical significance . These results are closely comparable to our previous results using the same techniques in patients with suspected acute myocarditis [In order to assess whether T1-mapping offers any incremental value over conventional CMR techniques T2W, LGE) in the detection of myocarditis, patients were further stratified into subgroups according to their diagnostic certainty based on edema (T2W) and LGE imaging as used in typical clinical settings  demonstrated both edema and LGE patterns typical of myocarditis. They had more severe myocardial injury, as evidenced by a significantly higher Troponin I level and lower EF than other patient subgroups and controls . Group I patients also had significantly more edema and LGE compared to controls and other patient subgroups .Group II patients (edema- LGE+) did not fulfill criteria for edema but demonstrated typical LGE patterns. Reasons included not meeting current T2 SI cut-off values for edema despite good image quality (n = 8), and non-diagnostic image quality due to poor breath-holding (n = 2) or tachyarrhythmia (n = 2). These patients suffered less severe myocardial injury, with a significantly lower median Troponin I level, smaller areas of LGE than Group I patients  and a mean EF no different from controls.Group III patients  did not demonstrate edema or LGE on CMR. Three patients with difficulty breath-holding had non-diagnostic dark-blood T2W and LGE (including single shot LGE) imaging, while the rest did not demonstrate findings despite good image quality. These patients had a very low median Troponin I level (0.48 μg/L) and a mean EF no different from controls.T1-mapping, using a threshold of T1 ≥ 990 ms , was ablFurther information on tissue characterization may be extracted from native T1-maps using incremental thresholds  allows the simultaneous quantification of myocardial involvement as well as visualization of the topography of injury within the affected myocardium, providing important information such as the presence of a non-ischemic pattern of injury.In this work, we have shown for the first time that, in acute myocarditis, whole-heart T1-mapping: (1) can diagnose extra cases with small areas of focal injury not detected by T2W and LGE imaging; (2) detects a larger extent of myocardial involvement than T2W and LGE methods without increasing the number of false positive findings, and; (3) can demonstrate patterns of non-ischemic injury similar to LGE imaging, without the need for exogenous contrast agents.Consistent with the current understanding of acute myocarditis, the findings of significantly increased T2 SI and T1 times in these patients support the notion that edema and inflammation are major components in the acute pathophysiologic process . While aAs a method for imaging edema, T1-mapping may replace dark-blood T2 with statistically better diagnostic performance in detecting changes of acute myocarditis as a single criterion  CARDIAC GATED MAPPING OF T1. September 29, 2010. All rights sold exclusively to Siemens Medical Solutions.US patent pending 61/689,067: SKP, MDR. COLOR MAP DESIGN METHOD FOR IMMEDIATE ASSESSMENT OF THE DEVIATION FROM ESTABLISHED NORMAL POPULATION STATISTICS AND ITS APPLICATION TO CARDIOVASCULAR T1 MAPPING IMAGES.VMF: contributed substantially to the conception and design of the study, recruitment of subjects, data acquisition, data processing, analysis, interpretation and drafting the manuscript; SKP contributed substantially to writing the dedicated software for data post-processing, data analyses, interpretation and generation of T1- and colored T1-maps; EDA, JMF, NN and CH contributed to data acquisition; AK contributed to recruitment of subjects; TDK, RPC, MGF, MDR have critically revised the manuscript; SN participated in the design and coordination of the study and critically revised the manuscript. All authors contributed to critical revision of, reading and approving the final manuscript.CMR Image acquisition parameters.Click here for file


Postnatal outcome of fetuses with hypoplastic left heart syndrome (HLHS) is mainly determined by right ventricular function. In the present study we used spatio-temporal image correlation (STIC) to assess right ventricular function of fetuses with HLHS.+0 and 37+6 weeks of gestation. Right ventricular end-diastolic volume (RVEDV) and right ventricular end-systolic volume (RVESV) were determined using the virtual organ computer-aided analysis software, and the parameters of right ventricular function were calculated.Three-dimensional ultrasound with STIC technique was used to acquire heart images from fetuses that had HLHS and the normal controls, between 24P < 0.001). There were no significant differences in the parameters between fetuses with and without a visible left ventricular cavity (P > 0.05). Compared to fetuses with HLHS plus mild tricuspid regurgitation (TR), fetuses with HLHS plus severe TR exhibited lower right ventricular stroke volume (RVSV), right ventricular cardiac output (RVCO) and standardized RVCO (P < 0.05). The right ventricular ejection fraction (RVEF) was significantly lower in HLHS fetuses that had severe TR (P < 0.001).Both RVEDV and RVESV were found to be significantly higher in fetuses with HLHS as compared to that in normal controls (As the right ventricle is solely responsible for maintenance of circulation, the right ventricular systolic function undergoes compensatory enhancement in fetuses with HLHS and mild TR, compared to that in normal controls. Size of the left ventricle does not significantly affect the right ventricular function in HLHS. However, right ventricular systolic function may be impaired prenatally in HLHS fetuses that have severe TR. The hypoplastic left heart syndrome encompasses a spectrum of cardiac malformations that are characterized by significant underdevelopment of the components of the left heart and the aorta, including the left ventricular cavity and mass . Its maiFour-dimensional spatio-temporal image correlation (STIC), which correlates the three-dimensional volume with cardiac phase, has been extensively used in screening and diagnosis of fetal cardiac defects –14. HoweIn the present study, we used STIC in combination with VOCAL to compare the cardiac function parameters, such as stroke volume, cardiac output and ejection fraction, between fetuses with HLHS and gestational age-matched normal controls.The study was approved by the Clinical Ethics Committee at the Second Xiangya Hospital of the Central South University in Changsha. All participating subjects were informed of the sensitivity, accuracy and limitations of the ultrasound examination. Written informed consent was obtained prior to enrollment.Forty-nine pregnant women carrying fetuses with HLHS, and 180 pregnant women carrying normal fetuses were enrolled during routine prenatal ultrasound examinations conducted between September 2008 and October 2014. Only cases with situs solitus, atrio-ventricular concordance and ventriculo-arterial concordance were included in the study. Subjects with other cardiac comorbidities such as, transposition of great arteries, double outlet right ventricle and atrioventricular septal defect were excluded.Severe TR was defined according to the following parameters: the maximum velocity of TR is above 2 m/s, with an area covered by the jet > 25 % of the atrium, reverse or absent blood flow during atrial systole in the ductus venous , 16.2. Fetal biometric measurements were performed on each scan. Subsequently, fetal echocardiography was performed by an expert and the STIC volume acquired.Voluson 730 Expert and Voluson E8  ultrasound systems were used with obstetric preset. The Doppler energy was set at < 100 mW/cmPrior to STIC volume acquisition, fetal heart preset was selected and four-chamber view was displayed. The image was magnified with the heart occupying 1/3 to 1/2 of the screen. The gray scale image contrast was adjusted to afford a clear delineation of the four chambers of the fetal heart. After initial preparation, the STIC function was activated. Based on the size of fetal heart and the frequency of fetal movement, the acquisition time was set at 10–15 s and the scanning angle was set between 25 and 35°. The sample box included the whole fetal heart and its adjacent structures. Volume data was acquired when: 1) the probe was held still; 2) no fetal movement was present; 3) at least three complete cardiac cycles were included; 4) the fetus was in a supine position, and the angle between ultrasound beam and the heart was < 30°; and 5) There was no or very little shadowing from the ribs in the fetal heart. Qualified images were saved for off-line analysis.4DView  was used to analyze the acquired volume data. In plane A, the fetal heart was repositioned in such a manner that the apex was in an upright position and the interventricular septum was perpendicular to the X axis. The X, Y, and Z axes were rotated to obtain the maximum visualization of the right ventricular cavity. Then select the image pseudo color for Sepia and SRI 5. After adjusting the brightness and contrast, the image was enlarged to 1.3 times and the cine speed reduced to 25 %. Since isovolumic contraction and relaxation time was short and had little impact on the ventricular volume, we defined end-diastole as the instant when the atrioventricular valve has just closed, and end-systole as the instant just prior to the opening of the atrioventricular valve.°, and the reference point was placed in the right ventricle. After setting these parameters, the software automatically generated 12 images at different rotation angles for tracing. The endocardium was outlined on each image. The trabeculae and muscle bundles were considered as a part of the ventricular cavity. After the initial tracing was obtained, the curve was further trimmed in each plane to ensure accuracy. The software automatically calculated the RVEDV and RVESV. These measurements were performed in three consecutive cardiac cycles by the same examiner and the averages were used for further analysis.VOCAL mode was used to estimate the volume of right ventricle. Since the endocardium of the right ventricle is rough and full of trabecular muscles, we traced the inner surface of ventricle manually. The rotation angle was set to 15The RVEDV and RVESV measurements were used to calculate the following parameters: right ventricular stroke volume (RVSV), right ventricular cardiac output (RVCO), right ventricular ejection fraction (RVEF), and RVCO/estimated fetal weight (EFW) . In addiParents of the affected fetuses were informed of the findings and the potential outcomes. If the pregnancy was terminated, fetal autopsy was performed only after the written informed consent of the parents.Inter-examiner and intra-examiner reproducibility was assessed separately by repeat examinations performed in a random sample of 30 cases each. For inter-examiner reproducibility, coefficient of variation was determined after re-examination by two examiners, while that for intra-examiner reproducibility was determined after re-examination by the same examiner 2 weeks after the initial examination.P-value < 0.05 was considered statistically significant.Statistical analysis was performed using SPSS 17.0 . All data are expressed as mean ± standard deviation (SD). Inter-group differences were assessed by Analysis of Covariance (ANCOVA), with gestational age considered as a covariate. A A total of 49 cases of prenatal HLHS were enrolled. Parents of 42 cases opted for termination of pregnancy, while 4 fetuses died in utero. Diagnosis was confirmed on autopsy in all 46 cases. The remaining 3 cases were lost to follow-up.+0 and 27+6 weeks, 51 cases between the 28+0 and 31+6 weeks, and 45 cases between the 32+0 and 37+6 weeks. Fetal RVEDV, RVESV and other right cardiac function parameters were calculated in these cases : 55 cases between the 24es Figs.  and 2a.F+0 and 27+6 weeks, 13 cases between the 28+0 and 31+6 weeks, and 8 cases between the 32+0 and 37+6 weeks. Fetal RVEDV, RVESV and other right cardiac function parameters were calculated in these cases : These included, 18 cases between the 24ses Fig. , c.P < 0.001). No significant difference in terms of cardiac function parameters were observed between those with (N = 26) and without (N = 13) visible left ventricular cavity (P > 0.05) , those with severe TR (N = 10) had significantly increased RVEDV (P < 0.05) and RVESV (P < 0.001), but lower RVSV, RVCO, standardized RVCO  (P < 0.05) and RVEF (P < 0.001). No significant difference in RVEF was observed between fetuses with HLHS plus mild TR and normal controls (P > 0.05) (Table Compared with fetuses with HLHS and mild TR (5) Table  and 4. TThe inter-examiner reproducibility was 92.5–88.2 %, while the intra-examiner reproducibility was 93.4–89.1 %.N = 12), frequent fetal movement (N = 9), and low image quality (N = 15). As a result, a total of 190 fetuses with acceptable STIC images , were studied. The overall success rate of data collection in the study was 84.07 %. Our study suggests that measurements of fetal ventricular volume in the different cardiac phases can be done with a high feasibility using STIC technology, which is an available tool for obtaining data on fetal cardiac volume throughout the cardiac cycle, and assess fetal cardiac function under both physiological and pathological conditions.In the present study, a total of 226 fetuses were initially included. However, data acquisition and analysis was not successful in all cases due to poor fetal positioning (Fetuses with HLHS have a left ventricle with either a very poor function or no function at all, due to which sufficient amount of blood cannot be pumped into the aorta. This effectively renders the right ventricle as the only functional ventricle for maintenance of the systemic and fetal pulmonary circulation , 19. SurIn the present study, fetuses with HLHS had a significantly increased RVEDV and RVESV as compared to that in their gestational age-matched controls, which may represent a compensatory mechanism. Further, no difference in RVEF was observed between the affected fetuses with mild TR and the normal controls, which suggests that fetuses with HLHS plus mild TR tend to maintain a relatively normal right ventricular systolic function. Our study also suggests that the presence of hypoplasia or atresia of left ventricle and/or ascending aorta could severely impair the left ventriclar function, thus rendering the right ventricle as solely responsible for maintenance of circulation. Therefore, increased RVCO becomes necessary in fetuses with HLHS, only this can ensure that the fetal circulation meets the needs of growth and development of the fetus in utero, while the compensaory increase of right ventricular volume and compensatory enhancement of right ventricular systolic function in fetus with HLHS is to ensure that the appropriate increase of RVCO.To understand whether the size of the left ventricle had any effect on the right ventricular function, we further divided the affected fetuses into two subgroups: HLHS with and without a visible left ventricular cavity. No significant differences were noted between these two subgroups in terms of right ventricular volume and cardiac function parameters, which indicates that the absence of left ventricle did not have any impact on the right ventricular function, which is consistent with the findings from other recent studies , 19. ForAccording to the available literature, severe TR rarely causes intrauterine death in HLHS. However, in fetuses that survive to term, severe TR places the children undergoing postnatal surgery at higher risk , 23, 24.For affected fetuses with a narrow foramen ovale or an intact atrial septum, there are few cardiac function parameters other than pulmonary vein Doppler indices that can be used to guide prenatal counseling and inform postnatal management of single ventricular circulation . Since cThe main limitation of this study is that there is no postnatal follow-up to test the fetal findings as parents chose to terminate the pregnancy. Poor image quality was one of the factors that could have affected the data analysis, as the STIC technology requires a high quality volume set. Further, the image acquisition process is liable to be affected by a variety of factors, including fetal size, fetal position, fetal movements, fetal rib shadowing, amniotic fluid volume and by maternal factors. Owing to the relative rarity of cases, the small sample size is another factor, which may have reduced the power of the statistical analysis. Thus, further studies with larger sample sizes are warranted.The size of the left ventricular cavity in fetuses with HLHS does not significantly affect the right ventricular function. Fetuses with HLHS and mild TR had enhanced right ventricular systolic function compared to normal controls, which probably represents a compensatory mechanism. However, those with severe TR are likely to have impaired right ventricular systolic function in utero, which requires a prompt clinical intervention.