This 3D motion‐corrected undersampled signal matched (MUST) T2 map is achieved by combining an undersampled motion‐compensated T2‐prepared Cartesian acquisition with a high‐order patch‐based reconstruction.To enable free‐breathing whole‐heart 3D T2 mapping acquisition consists of an electrocardiogram‐triggered, T2‐prepared, balanced SSFP sequence with nonselective saturation pulses. Three undersampled T2‐weighted volumes are acquired using a 3D Cartesian variable‐density sampling with increasing T2 preparation times. A 2D image‐based navigator is used to correct for respiratory motion of the heart and allow 100% scan efficiency. Multicontrast high‐dimensionality undersampled patch‐based reconstruction is used in concert with dictionary matching to generate 3D T2 maps. The proposed framework was evaluated in simulations, phantom experiments, and in vivo  with 1.5‐mm3 isotropic resolution. Three‐dimensional MUST‐T2 was compared against standard multi‐echo spin‐echo sequence (phantom) and conventional breath‐held single‐shot 2D SSFP T2 mapping (in vivo).The 3D MUST‐T2 showed high accuracy in phantom experiments (R2 > 0.99). The precision of T2 values was similar for 3D MUST‐T2 and 2D balanced SSFP T2 mapping in vivo . Slightly longer T2 values were observed with 3D MUST‐T2 in comparison to 2D balanced SSFP T2 mapping . Preliminary results in patients demonstrated T2 values in agreement with literature values.Three‐dimensional MUST‐T2 mapping with high isotropic resolution in about 8 minutes, achieving accurate and precise T2 quantification of myocardial tissue in a clinically feasible scan time.The proposed approach enables free‐breathing whole‐heart 3D T A map of T2 relaxation times is then generated by fitting the series of weighted images to an exponential decay model on a pixel‐by‐pixel basis. Current clinical protocols usually perform myocardial T2 mapping with a 2D single‐shot SSFP (T2p‐SSFP), acquiring 3 T2‐prepared images in a single breath‐hold every 2 to 3 heartbeats to allow for full T1 recovery.Myocardial T2 mapping, particularly in hypertrophic cardiomyopathies in which the pathological tissues are often complex 3D structures with differing T2 values.2‐weighted images, due primarily to imperfect breath‐holding or variable heart rate.However, the use of 2D acquisitions with fairly thick slices and the associated partial volume effects undermine the full potential of myocardial T2 mapping approach with high isotropic spatial resolution may have the potential to increase diagnostic accuracy in patients with acute myocardial injury , as only a small fraction of the acquired data is accepted for reconstruction (referred to as low scan efficiency).Three‐dimensional myocardial T2 mapping still faces substantial technical challenges that in turn may limit its applicability in clinical practice. In this study, we sought to achieve high isotropic spatial resolution 3D Cartesian whole‐heart myocardial T2 mapping in a short and predictable scan time of about 8 minutes by combining a highly accelerated saturation‐based free‐breathing myocardial T2 mapping sequence with 2D image‐based navigator (iNAV) respiratory motion correction. A recently proposed high‐dimensionality undersampled patch‐based reconstruction (HD‐PROST)2 maps. The proposed framework was validated in simulations, phantom, and healthy subject experiments, while its initial clinical feasibility was shown for 2 patients with suspected cardiovascular disease.Notwithstanding the continued advancements, myocardial 3D T2Acquisitions were performed on a 1.5T MR scanner  with a dedicated 18‐channel body coil and a 32‐channel spine coil. Written informed consent was obtained from all healthy subjects and patients before undergoing MRI scans, and the study was approved by the National Research Ethics Service. Numerical simulations, reconstructions and analysis were performed on a workstation with a 16‐core dual Intel Xeon Processor .2.12 mapping sequence is shown in Figure SAT) from the data acquisition. The value of TSAT is set to the maximal available time allowed by the sequence to guarantee enough magnetization recovery before the next acquisition. This approach allows efficient imaging at every heartbeat, avoiding the use of multiple recovery periods.2 prepared pulse with variable TE (TET2prep) is performed, followed by a balanced SSFP readout. An adiabatic T2‐prep module (Silver‐Hoult type) is used because of its good insensitivity to B1 and B0 inhomogeneities.2‐weighted volumes are acquired sequentially with different T2 weightings .The proposed myocardial 3D motion‐corrected undersampled signal‐matched (MUST) T2‐prepared volumes. This trajectory samples the ky‐kz phase‐encoding plane following approximate spiral interleaves on the Cartesian grid with variable density along each spiral arm and with 2 successive spiral interleaves being rotated by the golden angle. A golden angle rotationA 3D Cartesian variable‐density trajectory with spiral profile order2‐mapping sequence. Two‐dimensional translational motion is estimated using a template‐matching algorithm with normalized cross correlation as similarity measure, with the template manually selected around the heart during acquisition planning. Motion compensation of the 3 volumes is performed by modulating the k‐space data with a linear phase shift to a reference respiratory position selected at end‐expiration.A 2D low‐resolution iNAV2.22‐weighted volumes. The HD‐PROST reconstruction exploits local , nonlocal , and contrast  redundancies of the 3D volumes in an efficient low‐rank formulation. The reconstruction is formulated as an iterative 2‐step process: (1) an L2‐norm regularized parallel‐imaging reconstruction using the denoised multicontrast data from step 2 as a prior (optimization 1); and (2) an efficient high‐order low‐rank patch‐based denoising , reflecting the degree of structural information within each patch, and (2) the high‐order singular value truncation parameter (pλ = 0.1 in this study) that controls the amount of regularization.Multicontrast HD‐PROSTThe HD‐PROST reconstruction was implemented and performed offline using the algorithm described in Bustin et al.2.32 mapping, the acquisition of each T2‐weighted image is followed by a resting period of about 2‐3 heartbeats to allow for full longitudinal magnetization relaxation. Numerical extended phase graph simulations were first performed to investigate the impact of removing recovery heartbeats and integrating saturation pulses on the longitudinal magnetization of 3D MUST‐T2 for tissues with different relaxation times T1. Simulations were performed for a T2 of 50 ms and varying T1 values (ranging from 700 ms to 1200 ms) with and without saturation pulses. Other relevant parameters used in the simulations were TET2prep = 55 ms, TR = 3.2 ms, trigger delay = 856 ms, data‐acquisition window of 100 ms, and a simulated heart rate of 60 beats per minute (bpm).Usually in myocardial T2.42 dictionaries are simulated using the extended phase graph formalism2 values. For both phantom and in vivo experiments, the dictionaries are calculated matching the subject‐specific acquisition parameters with T2s in the range [minimum : step size : maximum] of  ms. Simulations show that the proposed method is not dependent on the used T1 value (in the range of interest) for dictionary generation ; thus, T1 is kept constant at 1100 ms for the phantom and in vivo experiments. The T2 maps are obtained by voxel‐wise matching of the measured and normalized signal to the closest (minimum least squares) extended phase graph–based dictionary entry. The choice of dictionary‐based matching versus conventional mono‐exponential curve fitting is justified in Supporting Information Figure Three‐dimensional MUST‐T2.52 mapping sequence was evaluated in a standardized (T1MES) T1/T2 phantom containing 9 agarose‐based tubes with relevant cardiac T1 and T2 combinations .2 included TR = 3.13 ms, TE = 1.37 ms, flip angle = 90°, FOV = 187 × 187 × 156 mm3, 1.5 mm3 isotropic resolution, bandwidth = 908 Hz/pixel, data‐acquisition window = 100 ms, and TET2prep =  ms. Reference T2 relaxation times for each vial were obtained using a multi‐echo spin‐echo (SE) sequence with 8 TEs ranging from 10 ms to 640 ms. In addition, conventional ECG‐triggered 2D T2p‐SSFP was performed for comparison purposes with the following imaging parameters: 1.9 × 1.9 mm2 in‐plane resolution, slice thickness = 8 mm, TR/TE = 3.11/1.38 ms, linear k‐space reordering, bandwidth = 1184 Hz/pixel, TET2prep =  ms, flip angle = 70°, 3 recovery beats, and GRAPPA factor 2 with 36 k‐space autocalibration lines. The T2 relaxation times were obtained by mono‐exponential curve fitting for both the SE and T2p‐SSFP sequences.The proposed ECG‐triggered 3D MUST‐T2.5.12 accuracy was assessed by performing multiple 3D MUST‐T2 phantom acquisitions with different simulated heart rates . The trigger delay was set to 70% of the R‐R interval and ranged from 420 ms to 840 ms, while the saturation time TSAT was always set to the maximum allowed time (ranging from 370 ms to 790 ms). The acquisitions were performed fully sampled using the previously described variable‐density trajectory with spiral profile order sampling.The impact of heart‐rate differences on T2.5.22 on the accuracy of the T2 values, several phantom acquisitions were performed with different undersampling factors ranging from 1‐fold to 5‐fold (step size 1). Additional acquisition parameters included simulated heart rate of 60 bpm, trigger delay of 680 ms, and saturation time TSAT = 630 ms.To study the impact of accelerating 3D MUST‐T2.5.32, SE, and 2D T2p‐SSFP sequences. For each vial, the average T2 value was measured, and agreement among SE, 2D T2p‐SSFP T2 values, and the proposed approach was assessed using linear regression.Circular regions of interest were drawn on each vial for 3D MUST‐T2.62.6.12 mapping using the proposed 3D MUST‐T2 acquisition approach. Relevant scan parameters included FOV = 320 × 320 × 84‐108 mm3, slice oversampling = 22%, 1.5‐mm3 isotropic resolution, flip angle = 90°, TET2prep =  ms, subject‐dependent middiastolic trigger delay (mean: 672 ms [range: 521‐952 ms]), acquisition window (mean: 97 ms [range: 80‐108 ms]), TSAT (range: 470‐900 ms), acceleration factor of ×5, 14 linear ramp‐up pulses for iNAV, and Hanning‐filtered sinc pulse with a duration of 1 ms and time‐bandwidth product of 4.5. To ensure adequate fat suppression, a spectral presaturation with inversion recovery was applied before imaging. All 3D MUST‐T2 mapping acquisitions were performed in the coronal plane.Ten healthy subjects  with no history of cardiovascular disease underwent ECG‐triggered free‐breathing 3D whole‐heart T2p‐SSFP T2 mapping2‐weighted images.2 maps were obtained by mono‐exponential curve fitting.Conventional 2D T2.6.22 sequence was assessed in 2 patients  with suspected cardiovascular disease. The same acquisition and reconstruction parameters as in the healthy subject study were used. The patient‐specific saturation times were TSAT = 525 ms  and TSAT = 595 ms . Conventional 2D T2p‐SSFP T2 mapping was acquired for each patient with the same parameters as in the healthy subject study.The feasibility and preliminary clinical performance of the proposed 3D MUST‐T2.6.32 maps were reformatted in the short‐axis view to match the 2D T2p‐SSFP slices. Regional differences in left ventricular T2 relaxation times were assessed according to the 16‐segment model of the American Heart Association.2 measurements were reported as mean ± SD and assessed using the Student's t‐test. Statistical differences in regional T2 values among reformatted basal, midventricular, and apical short‐axis slices were analyzed using repeated‐measures 1‐way analysis of variance with Bonferroni post hoc comparisons. All statistical analyses were performed using MATLAB , and statistical significances were defined as a P‐value < .05.The 3D MUST‐T33.11 relaxation times (ranging from 700 ms to 1200 ms). Although a clear dependency was observed when no saturation pulse was applied, necessitating about 2‐3 resting periods to recover 96% of the signal intensity  is depicted in Figure 3.22 values obtained in the phantom experiments when increasing the simulated heart rate (from 50 bpm to 100 bpm) are depicted in Figure 2 relaxation times measured with the proposed 3D MUST‐T2 sequence showed no to little sensitivity to change of heart rate for all vials in comparison to SE reference measurements.The average T2 values obtained with the proposed 3D MUST‐T2 approach in phantom is shown in Figure 2 and the ground‐truth T2 values obtained with SE, with high coefficients of determination (R2 > 0.99) for all acceleration factors (×1 to ×5), suggesting high accuracy of the proposed 3D sequence even for high acceleration factors. Lower linear correlation (R2 = 0.95) was observed for conventional 2D T2p‐SSFP in comparison to reference SE measurements. Bias between SE and 2D T2p‐SSFP with linear order acquisitions has been reported previously.The accuracy of the T2 agreement for all 31 slices of 3D MUST‐T2  for short T1 myocardium , 0.6 ms  for medium T1 myocardium , and 1.4 ms  for long T1 myocardium .Bland‐Altman analysis demonstrated good T3.3All healthy subject and patient acquisitions/reconstructions were performed successfully, and analysis results are reported hereafter.3.3.12 sequence in healthy subjects was 6 minutes 43seconds ± 1 minute 37 seconds  with 100% scan efficiency. Translational motion estimation and correction was performed in about 20 seconds, whereas the average reconstruction time (including HD‐PROST reconstruction and dictionary matching) was about 3 minutes. Representative T2 maps from 3 healthy subjects acquired with the proposed 3D MUST‐T2 sequence and the conventional 2D T2p‐SSFP sequence are shown in Figure 2 and breath‐held 2D T2p‐SSFP show comparable visualization of the left ventricle and surrounding structures . Reconstructed T2 maps from additional healthy subjects are shown in Supporting Information Figure The average acquisition time of the proposed free‐breathing 3D MUST‐T2 and 2D T2p‐SSFP mappings are depicted in Figure 2 values over the whole myocardium was observed with 3D MUST‐T2 in comparison to 2D T2p‐SSFP mapping . We found no statistical differences in regional T2 values between segments with 3D MUST‐T2 for all subjects (P = .6). A small overestimation of septal T2 values was observed with 3D MUST‐T2 in comparison to 2D T2p‐SSFP mapping with linear k‐space reordering . There were no statistical differences in mean T2 values with 3D MUST‐T2 among basal, midventricular, and apical slices for all subjects (P = .655).Bull's eye plots based on the American Heart Association's 16‐segment model of the left ventricle obtained with 3D MUST‐T2 values is shown in Figure 2 measurements obtained from 3D MUST‐T2 in vivo showed no significant correlation with heart rate .The effect of heart‐rate differences across healthy subjects on T2 approach are shown in Figure 2‐weighted images and the corresponding T2 maps are included. No noticeable residual undersampling artifacts were observed on the native T2‐weighted images the and corresponding T2 maps for the entire left ventricle.Eight short‐axis slices of the left ventricular myocardium for 1 representative healthy subject obtained with the proposed 3D MUST‐T2 acquisitions were performed with isotropic spatial resolution and whole‐heart coverage, the T2 maps can be reformatted in any arbitrary plane. This advantage is best appreciated in Figure Because MUST‐T2 maps of 2 healthy subjects are shown with and without 2D translational motion correction. Motion‐corrected T2 maps result in better visualization of the myocardium as compared with the non‐motion‐corrected T2 maps, which show some spatial blurring.The need for using 2D iNAVs to correct for respiratory motion is shown in Supporting Information Figure 3.3.22 sequence were 7 minutes 23 seconds  and 8 minutes 43 seconds . Figure 2 map slices for the 2 patients, using the proposed 3D MUST‐T2 framework compared with the current clinical reference maps (breath‐held 2D T2p‐SSFP). The proposed 3D MUST‐T2 produces T2 maps with visual appearance comparable to the conventional 2D T2p‐SSFP technique. The mean septal T2 relaxation times were similar between the 2 techniques .No cardiac findings were observed in the patient study. The acquisition times of the proposed 3D MUST‐T42 mapping that combines 2D translational respiratory motion correction with a golden‐angle variable‐density spiral‐like Cartesian trajectory and a recently introduced HD‐PROST reconstruction. The proposed 3D MUST‐T2 approach enables accurate and precise high‐resolution isotropic (1.5 mm3) 3D whole‐heart T2 mapping acquisitions in a fast and predictable scan time.In this study, we proposed a framework for highly accelerated free‐breathing whole‐heart T2 mapping framework was assessed in simulations, phantom experiments, and 10 healthy subjects, while initial clinical feasibility was demonstrated in 2 patients with suspected cardiovascular disease.The performance of the proposed 3D T2 uses a saturation pulse to reset the magnetization immediately after the R‐wave, as proposed by Ding et al,2 mapping techniquesThree‐dimensional MUST‐T2 values (R2 > 0.99) with respect to reference SE measurements. Besides the use of an efficient undersampling trajectory, the acquisition of low‐resolution 2D iNAVs at every heartbeat also permits a substantial reduction in scan time by allowing 100% respiratory scan efficiency (no data rejection) and predictable scan time,2 mapping techniques based on diaphragmatic navigator‐gated acquisition.2 mapping techniques have been proposed to allow for 100% scan efficiency and predictable scan time. Van Heeswijk et al2 maps with resolution of 1.7 mm3 in a predictable scan time of about 18 minutes at 3 T, while Basha et al2 was exploited to acquire in vivo isotropic whole‐heart Cartesian T2 maps in clinically feasible scan times (about 8 minutes), whereas a fully sampled acquisition would have required more than 35 minutes. The total imaging time for 3D MUST‐T2 was affected primarily by the subject's heart rate and the number of slices needed to cover the whole heart in the anterior–posterior direction. For comparison, the conventional breath‐hold 2D T2p‐SSFP sequence would have required between 5 and 7 minutes to cover the entire heart . The proposed 3D T2 mapping sequence can also be performed with lower anisotropic resolution  were in good agreement with in vivo values published in a previous study at 1.5 T with centric ordering  versus linear (2D T2p‐SSFP) k‐space ordering, as observed by Giri et al.2 preparation pulses, could also explain this overestimation in vivo and will be explored further.The acquisition of undersampled data comes, however, at the cost of significant loss of information that needs to be recovered. Multicontrast HD‐PROST reconstruction takes advantage of the local, nonlocal, and contrast redundancies found in the T2 values in vivo did not show significant deviations from the conventional 2D T2p‐SSFP acquisitions  and were similar to previously reported values at 3 T.2‐weighted images, noise being a severe side effect of saturation‐based MR mapping techniques.Although high acceleration factors were reached with the proposed 3D sequence, precision of T2 values by pregenerating a dictionary representative of the proposed T2 mapping sequence, and whose elements are composed of simulated signal evolution curves.2 values acquired with both 3D MUST‐T2 and conventional T2p‐balanced SSFP, whereas a T2 bias was observed with conventional mono‐exponential fitting for both methods . Further speedup to reach subminute runtime could be achieved by implementing the reconstruction on multiple GPUs and using coil compression strategies.Translational motion estimation and correction was performed inline in the scanner software, while HD‐PROST reconstruction and dictionary matching were performed offline. The efficient multithreaded implementation of HD‐PROST allowed for fast T2 is based on a T2‐prepared sequence that is used commonly in coronary MRA.2‐weighted volume , resulting in degraded image quality. Higher amplitude in respiratory motion of the heart, as provided by the 2D iNAVs, was observed in patients compared with healthy controls  in a clinically feasible scan time (< 8 minutes with 100% scan efficiency and predictable scan time). The proposed 3D MUST‐T2 framework achieved accurate T2 quantification in phantom and in vivo with fast acquisition. Three‐dimensional MUST T2 mapping may have the potential to aid the management of many cardiomyopathies in which fast and efficient free‐breathing acquisitions are key to patient comfort, whereas high isotropic resolution is crucial to accurately map tissue heterogeneity. Further studies to assess the clinical utility of 3D MUST‐T2 mapping in patients with myocardial inflammation are now warranted.A novel approach was developed to enable free‐breathing whole‐heart 3D TDr. Radhouene Neji is employed by Siemens Healthcare, Frimley, United Kingdom.FIGURE S1 A 3D Cartesian variable‐density trajectory was used to allow for fast acquisition of multiple T2‐weighted images. The Cartesian trajectory with spiral order samples the ky‐kz phase‐encoding plane following approximate spiral interleaves on the Cartesian grid with variable density along each spiral arm. In this sketch, the 2 first acquired spirals are shown for each contrast . A golden angle rotation between successive spirals and successive contrasts is applied to introduce incoherently distributed aliasing artifacts along the contrast dimension, and noise‐like artifacts in the spatial dimensionFIGURE S2 Flowchart of the optimization 2 of the proposed HD‐PROST. Denoising of multiple T2‐weighted images is performed using a 3D block matching, which groups and unfolds similar 3D patches in the noisy multicontrast images to form a low‐rank 2D matrix. A third‐order tensor is formed by stacking the T2 contrast dimension on the third dimension. The high‐order tensor of size N (number of pixels in each patch) × K (number of similar patches within a neighborhood) × L (number of T2 contrasts) admits a low multilinear rank approximation and can be compressed through high‐order tensor decomposition by truncating the multilinear singular vectors that correspond to small multilinear singular values. The outputs of this step are the denoised multicontrast images that are then used in the joint regularized reconstruction step (optimization 1) as prior knowledge. Reconstruction parameters used in this study are shown (bottom row). We refer the reader to Bustin et alλp, threshold valueFIGURE S3 Simulations of the proposed T2 mapping sequence were performed using the EPG formalism to assess the effect of T1 in the EPG‐based dictionary on the matched T2 value. Signal evolutions for different T1 (from 850 to 1200 with a step size of 50 ms) and T2 (from 42 to 82 with a step size of 8 ms) were generated and matched to a dictionary simulated with fixed T1 (1100 ms) and varying T2s (similar to the one used in the phantom experiment). A, Matched T2 is plotted as a function of T1. B, The signal evolutions corresponding to short (T1/T2 = 800/52 ms), medium (T1/T2 = 1100/52 ms), and long (T1/T2 = 1300/52 ms) T1 myocardium were generated for the proposed sequence through EPG simulation. The obtained signal evolutions did not appear to differ, suggesting that the proposed 3D MUST‐T2 map sequence with dictionary‐based matching is independent of the T1 used in the EPG‐based dictionary . Therefore, for the phantom and in vivo experiments, we kept the T1 constant at 1100 msFIGURE S4 Conventional mono‐exponential fitting and dictionary‐based matching for T2 T2p‐SSFP T2 mapping in comparison to the proposed 3D MUST‐T2 sequence for the phantom study. The proposed 3D acquisition with mono‐exponential fitting is also included for comparison purposes. Accurate phantom T2 values, in agreement with reference spin echo, were obtained with the proposed 3D MUST‐T2 sequence with dictionary‐based matching; however, bias is observed with the proposed acquisition when mono‐exponential fitting is used. Bias is also observed with the conventional (linear phase encoding) 2D T2p‐SSFP mapping with mono‐exponential fitting; however, this bias is significantly reduced when dictionary‐based matching is usedFIGURE S5 Spatial T2 uniformity over the slice direction is assessed for the phantom study for 3 vials . The solid line is the average difference between gold‐standard spin echo and the proposed 3D MUST‐T2 mapping sequence, and the dashed lines represent the mean ± 2 SDs between the 2 techniques. Good T2 uniformity can be observed with the proposed technique. The mean difference in T2 for the vial corresponding to short T1 myocardium was −0.6 ms [±95% confidence interval [CI] = −2.1/0.89 ms), −0.6 ms [±95% CI = −3.7/2.5 ms) for the medium T1 myocardium, and −1.4 ms [±95% CI = −4.9/2.0 ms) for the long T1 myocardiumFIGURE S6 The T2 maps obtained using the proposed free‐breathing 3D MUST‐T2 mapping sequence and the conventional breath‐held 2D T2p‐SSFP sequence are shown for 3 additional healthy subjects. The 3D MUST‐T2 slices were reformatted to short axis to match the 2D T2 map acquisitions. Representative 16 American Heart Association segments are shown to illustrate how much spatial information was considered for T2 calculation. Acquisition times are expressed as minutes:secondsFIGURE S7 Axial view of T2 maps acquired using the proposed 3D T2 mapping sequence on 3 healthy subjects. Number of slices was adjusted per subject to cover the left ventricle in the anterior–posterior directionFIGURE S8 Impact of iNAV‐based beat‐to‐beat translation motion correction on 3D MUST‐T2 map is shown for 2 healthy subjects. A, Reconstructed T2‐weighted images (TET2prep = 55 ms) are shown before and after motion correction with the corresponding T2 maps. Better visualization of the myocardium can be observed after motion correction with clear delineation of cardiac structures and myocardial walls. Note the blurring observed on the non‐motion‐corrected T2 maps. B, Plots showing the intensity profiles taken on the T2‐weighted images through the heart–liver interfaceFIGURE S9 A, Foot–head respiratory displacements of the heart obtained from the 2D image navigators at each heartbeat are shown for 2 representative healthy subjects (left) and 2 patients (right). The end‐expiration position is used as reference for translational motion estimation. Although regular breathing patterns can be observed on the healthy subjects, more irregular breathing patterns with strong motion amplitudes are observed on patients 1 and 2. B, Average R‐R intervals are shown for each healthy subject and patient. Patient 1 presented with irregular cardiac rhythm (R‐R = 838 ± 211 ms)Click here for additional data file.


Prolonged breath holding results in hypoxemia and hypercapnia. Compensatory mechanisms help maintain adequate oxygen supply to hypoxia sensitive organs, but burden the cardiovascular system.The aim was to investigate human compensatory mechanisms and their effects on the cardiovascular system with regard to cardiac function and morphology, blood flow redistribution, serum biomarkers of the adrenergic system and myocardial injury markers following prolonged apnoea.Seventeen elite apnoea divers performed maximal breath-hold during cardiovascular magnetic resonance imaging (CMR). Two breath-hold sessions were performed to assess (1) cardiac function, myocardial tissue properties and (2) blood flow. In between CMR sessions, a head MRI was performed for the assessment of signs of silent brain ischemia. Urine and blood samples were analysed prior to and up to 4 h after the first breath-hold.p < 0.05). Peripheral oxygen saturation, LV ejection fraction, LV fractional shortening, and heart rate decreased significantly (p < 0.05). Blood distribution was diverted to cerebral regions with no significant changes in the descending aorta. Catecholamine levels, high-sensitivity cardiac troponin, and NT-pro-BNP levels increased significantly, but did not reach pathological levels.Mean breath-hold time was 297 ± 52 s. Left ventricular (LV) end-systolic, end-diastolic, and stroke volume increased significantly .This prospective single-centre study was approved by the institutional ethics committee review board. It was retrospectively registered under ClinicalTrials.gov  contains supplementary material, which is available to authorized users. It is known from animal studies that hypoxia is associated with increased mean arterial blood pressure and altered myocardial morphometry due to increased left ventricular (LV) end-diastolic pressure with lengthening of end-diastolic and end-systolic myocardial fibres , 2. In h mmHg O2 , 7. Adeq mmHg O2 . The div mmHg O2 , 9, poss mmHg O2 . WhetherCardiovascular magnetic resonance (CMR) is a standard non-invasive method for functional analysis of the heart , which aThe aim of this study was to investigate cardiovascular effects during maximal apnoea in elite healthy subjects and to determine the accompanied blood flow redistribution. Cardiac biomarkers and serum markers of the adrenergic system were determined. Cerebral MRI was performed after maximal apnoea to detect potential brain injury.Inclusion criteria were experience in apnoea diving with a minimum breath-hold time of 270 s, a minimum age of 18 years, an unremarkable history of cardiac and lung disease, and the absence of long-term medication. Exclusion criteria were any contraindication to CMR or any known heart or lung disease. Participants were required not to drink caffeine-containing drinks and were instructed not to eat at least 8 h before the examination.All study subjects received an information sheet 14 days prior to the study. Informed consent was obtained from all participants prior to study inclusion. Participants were questioned about training protocols and diving experience.The study protocol comprised two apnoea sessions of individual maximum breath-hold combined with CMR measurements . Participants were asked to perform their usual pre-apnoea routines (yoga and breathing exercises). Fifteen minutes before CMR the participants were required to stop with their individual exercises and to breathe normally. A maximum of three deep inspirations prior to the final breath-hold was allowed. Hyperventilation was not allowed. Apnoea was performed as long as the individual subjects were able to withstand the breathing reflex.This “individual” approach close to personal best breath-hold amplifies the redistribution effects and supposedly exhibits the maximum effect on the cardiovascular system. Additionally, a brain MRI was performed at least 30 minutes after the first of the two breath-hold sessions to detect acute brain ischemia. Cardiac biomarkers and catecholamines were evaluated to detect cardiac damage . The protocol for the “functional cardiac session” consisted of retrospectively gated balanced steady state free precision cine imaging with 30 cardiac phases per slice. To assess functional changes under apnoea, three short axis  cines as well as a vertical long axis cine  were acquired repeatedly over the course of apnoea. T2-mapping – indicative of myocardial oedema - using a gradient-spin-echo technique was performed in the same three slices in short axis orientation as the steady state free precision cine images prior and immediately after maximal apnoea .MRI of the brain was performed using a 3 Tesla MRI scanner  using a dedicated head coil. The protocol comprised a transverse T2-weighted turbo spin echo (TSE), a transverse fluid attenuated inversion recovery (FLAIR), a transverse T2*, a sagittal T1-weighted 3D gradient echo, and a transverse as well as a coronal diffusion weighted imaging (DWI) sequence.The second CMR session was performed at least 4 h after the first “functional” cardiac session. This session was focused on flow measurements in the ascending and descending aorta, the pulmonary trunk, and both common carotid arteries using common 2D phase contrast imaging.early) and last completed imaging data set  of each maximum apnoea were compared. Global cardiac function at resting conditions (left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), stroke volume (LVSV), and ejection fraction (LVEF) were determined from the short axis  and normalized to the body surface area (BSA) using Mosteller’s formula [max), mean velocity (Vmean), mean flow (Qmean) and absolute stroke volume (SV) was assessed, respectively. T2 relaxation times were extracted from the T2 maps that were generated by using dedicated software . A circular region of interest (ROI) was then manually placed in the septal and lateral LV wall and averaged.Two radiologists blinded to the study protocol independently evaluated all images. The first (apnoea formula . LVEDV a formula . In shor2) and heart rate (HR) were measured continuously during both CMR sessions using a CMR-compatible device .Cerebral MRI was analysed by the same two radiologists for focal diffusion restrictions as a sign of acute cerebral ischemia, cerebral micro-bleedings, and incidental findings. Peripheral oxygen saturation  [Myocardial oxygen demand was estimated using the modified pressure work index as previously described  :\documenUrine was collected for baseline measurements 30 min before the first apnoea session started and 4 h thereafter, but before starting the second CMR session. Catecholamine levels, N-terminal pro-hormone of brain natriuretic peptide (NT pro-BNP), brain natriuretic peptide (BNP) and high sensitive troponin (hs-cT) were analysed from venous blood samples taken before, immediately after, 30 min, and 4 h after the first apnoea. All results (urine and blood samples) therefore reflect the effect of the first single breath-hold, but not those of repetitive apnoeal stages.NT-pro BNP measurements were performed immediately after blood collection under routine conditions with the LOCI™-based NT-proBNP assay for Dimension™ VISTA 1500 . For BNP, hs-cT, and catecholamine analysis, aliquots were stored at − 80 °C. BNP and hs-cT were measured using commercially available, specific immunoassays . Plasma catecholamine levels were analyzed using a catecholamine reagent kit  with a HPL Chromatography . Urine catecholamines were analysed by Bio Rad HPLC Agilent 1100 Series .p < 0.05.Data are presented as mean +/- standard deviation (SD). Statistical analysis was performed using GraphPad Prism  and SAS version 9.4 . Descriptive statistics are summarised as means and standard deviation (± SD). All parameters were compared using paired t-testing. Correlations were calculated using the Spearman’s rank correlation analysis. Statistical significance was defined as 2 and body mass index (BMI) 24.4 ± 2.3 kg /m2). Five of 17 divers regularly participate in various national and international competitions. The training frequency was 2.2 ± 1.6 training sessions a week. Training content and focus varied inter-individually. The breath-hold experience of all athletes was 4.5 ± 2.6 years. The personal breath-hold records were 5:20 ± 0:49 min. No comorbidities were found in any diver. Five divers have had a hypoxic blackout in their history.Seventeen elite apnoea divers (15 men) age of 40 ± 11 years were investigated under maximum breath-hold . SpO2 levels gradually decreased from 99 ± 1% to 74 ± 14% (p < 0.001) in the “functional cardiac session” and from 99 ± 1% to 77 ± 15% (p < 0.001) in the “flow session”. No hypoxic loss of consciousness was observed. Physiological data of each participant are listed in Table Maximal breath-hold time in the “functional cardiac session” was 413 s and maximal breath-hold time in the “flow session” was 483 s. Mean time of breath-hold in the “functional cardiac session” was 297 ± 52 s and 276 ± 80 s in the “flow session”  . Despite a significant decrease of HR   , with the decrease in the apical slice  and the midventricular slice , whereas only a non-significant trend was observed in the basal slice   Fig. , while L03) Fig.  decrease28) Fig. , LV-CO r88) Fig. . A reprep = 0.008). Additionally, ∆HR over the course of apnoea had a significant negative correlation with the change of LVEDV (∆LVEDV) . This was less prominent when ∆LVEDV was normalized to BSA . In contrast, there was only a weak correlation between ∆HR and an increase in ∆LVESV .Changes in HR (∆HR) over the course of apnoea Fig.  showed amax, Vmean, and Qmean increased significantly in the ascending aorta and the pulmonary trunk during apnoea, no changes were observed in the descending aorta, indicating a preferential blood flow distribution to the heart and the brain. In addition, both CCAs showed a significant increase in SV .While SV, Vsee Fig. , Vmean aWe found a decrease in HR (76 ± 23 bpm vs. 61 ± 12 bpm) and an increase in LVSV (75.6 ± 16.9 ml vs. 95.1 ± 32.6 ml) in this study. Using a previously reported increase of systolic and diastolic blood pressure from 135 ± 13 mmHg to 185 ± 25 mmHg  increasep > 0.05). Compared to baseline values, T2 relaxation times showed no significant change ; norepinephrine from 590 ± 197 pg/ml to 2063 ± 1703 pg/ml (p < 0.001)). Serum catecholamine levels returned to baseline values as early as 30 min post apnoea . Catecholamine levels derived from urine samples still showed a slight, but significant increase 4 h after apnoea compared to baseline conditions .Serum catecholamine levels see Fig. , b showep = 0.011) and to 53.8 ± 49.4 pg/ml (p = 0.037) 4 h after breath-hold   Fig. . CompareDWI revealed neither acute nor sub-acute signs of cerebral ischemia. In one participant, a clinically irrelevant singular micro-bleeding formation located in the brain stem was observed. In two participants, unilateral fluid collections of the mastoid were observed and reported. No further incidental findings were observed.In this present study, a holistic approach with state-of-the-art cardiac function evaluation, tissue characterization and biomarker analysis was performed to evaluate myocardial function, thoracic and supra-aortic blood flow, and their changes during maximal individual apnoea. The major findings of our study are a stepwise (1) increase of LVEDV, LVESV, LVSV and an unchanged CO, (2) decrease of LVEF and FS at the end of apnoea, (3) increase of supra-aortic blood flow without concurring flow changes in the descending aorta, and (4) an elevated hs-cT and NT-pro-BNP levels.In the present study we were able to demonstrate a significant LV dilatation along with an increased LVSV, which is in line with a previous study , where i2 decreased more profoundly in our study compared to the study from Pingitore et al. (from 99 ± 1% to 74 ± 14% vs. 97 ± 0.2% to 84 ± 2%) [Since the mammalian diving response to maximal voluntary apnoea considerably varies depending on the examined individual and the study setup, the at first apparently contradictory results of the three studies might be explained by the breath-hold duration , 9, 19. 84 ± 2%) .We found a relative increase in LVSV of 30 ± 48% during apnoea, but a decrease in FS and LVEF. FS depends on inter-ventricular dimensions and is affected by ventricular filling. Ejection fraction, in contrast, is a relatively load independent surrogate parameter for cardiovascular performance. In general, the efficiency of myocardial performance is determined by preload, afterload and contractility , 23. An NT-proBNP was elevated early after maximal apnoea. Although some authors describe BNP as an “emergency” cardiac hormone against ventricular overload , the obsIn addition, myocardial perfusion and oxygen consumption is dependant on various parameters. At the end of apnoea, HR decreases while SV and systolic and diastolic blood pressure increase. These physiological changes translate into an increase of estimated oxygen demand in our study from 8.5 ml/min/100 g to 9.5 ml/min/100 g (i.e. only by 11%). However, this increase in demand may be assumed to be outweighed by a theoretical increase of approximately 40% of coronary perfusion due to increase of the diastolic blood pressure. It is of note that these theoretical considerations are based on healthy subjects without any coronary morbidities.2 in case of apnoea [The human diving response  helps to preserve Of apnoea . These pf apnoea . The conf apnoea , 30. Duef apnoea , 25. In  Prolonged apnoea is not exclusively seen in breath-hold divers, also patients with obstructive sleep apnoea (OSA) show compensatory mechanisms to avoid brain damage . PatientPatent foramen ovale has been demonstrated to have a higher prevalence in patients with obstructive sleep aponoea compared to healthy controls, and is suspected to inrease nocturnal oxygen desaturation in these patients  and to eCardiac dysrhythmia or irregular heartbeats (mainly premature ventricular excitations) were observed in 14 of 17 divers at the end of apnoea and during the early recovery phase  might be limited at the end of apnoea due to e.g. motion artefacts (CMR), peripheral vasoconstriction (SpO2), and other technical restrictions. Blood pressure data is not available as invasive blood pressure measurement was not performed due to ethical considerations and automatic non-invasive blood pressure measurement failed due to the high and dynamic changes in blood pressure during apnoea. Due to the chosen CMR imaging protocol with only limited coverage of the RV, neither volumetric nor functional RV data are available. Future studies should also focus on effects of hypxoxia on pulmonary vasoconstriction and their effects on the RV function.Measurment accuracy  and in early recovery phase (e). (JPG 161 kb)


After more than half a century of clinical development, when Dr. DeBakey in 1962 and 1966and Dr. Cooley in 1969 first implanted devices in humans, mechanical circulatory support(MCS) has reached maturity and is now widely used for the treatment of advanced heartfailure (HF).Progress has been huge in recent years, with new challenges in candidate selection andclinical management amid the ongoing debate on the cost-effectiveness use of a finitefinancial healthcare resource, especially in countries like Brazil.Circulatory support devices of the first phase of development always sought to create thesystolic-diastolic pressure differential. It was inconceivable to imagine a continuousflow as a form of prolonged circulatory assistance. Thus, models such as Novacor,Electrical HeartMate and others were developed to allow patients to reach cardiactransplantation under improved clinical conditions.Since the work of Richard Wampler and OH Frazier with Hemopump in 1988 at Texas HeartInstitute, when they brought the advent of rotary blood pump technology, continuous-flowdevice therapy has emerged as a viable alternative in patients ineligible for cardiactransplantation.The advances in mechanical circulatory support have shared with that of hearttransplantation. Many of the decisions today in the treatment of heart failure are nowfocused on choosing patients for cardiac transplantation, mechanical support, orboth..Acute decompensated heart failure has emerged as a major public health problem over thelast decade. It is estimated that there are 1 million hospitalizations with a primarydischarge diagnosis of this syndrome annually, and that number is expected to increasesubstantially over the next two decades. The American Heart Association estimated thatthe prevalence of heart failure will increase 46% by 2030, resulting in more than 8million people affected by the disease,3.Heart failure has become the leading cause of hospitalization in people over 65 years ofage worldwide, even considering economic differences in countries. Reported death ratesappear excessive both during and after hospitalization, and readmission rates revealfailure in effective long-term care. The direct costs associated with treating the 5million Americans with chronic heart failure are mostly attributable to hospitalization.The US government estimates spending more than $26 billion a year on treating patientswith heart failure. In Brazil, of all hospitalizations in the country, 21% are from someetiology of heart failure.The registry of the International Society for Heart and Lung Transplantation reports theshort- and long-term outcomes of a heart transplant, with 1 and 10-year survival ratesof approximately 85% and 50%, respectively. However, the number of heart transplants,both in children and in adults, had little improvement in the last fewyearsWith this disproportionate number of heart transplants and the increasing number ofpatients with heart failure, ventricular assist devices (VADs) became the most commonsurgical procedure to support failing circulation, outstanding the frequency of hearttransplant .The shortage of donor organs enforces the establishment of waiting lists and priorityallocation of patients. This shortage also encouraged the research for therapeuticalternatives, with the possibility of helping circulatory support and promptavailability when needed..Improvements in device technology have made VADs an attractive alternative for thetreatment of end-stage HF. More reliable systems have enabled bridge to transplant (BTT)therapy. The use of VADs for this group of patients is a Class IIa-C recommendation. Anincreasing number of patients with end-stage HF who are ineligible for a transplant canbe implanted with VADs as destination therapy (DT), in order to improve survival andquality of life (Class IIa-B recommendation)versus the patient'schances of surviving the complications of LVAD therapy. Durable VAD therapy inpatients with end-stage HF demands a multidisciplinary approach in experiencedhigh-volume centers, with a transplant background. There is a constant 24/7 need.As mentioned, the leading indication for LVAD therapy is no longer BTT but DT in patientswho are ineligible for a heart transplant. Deciding on either strategy requires anevaluation of the patient's natural course with HF .In the 1990s, a large number of patients were bridged to transplant with LVADs. TheRandomized Evaluation of Mechanical Assistance for the Treatment of Congestive HeartFailure (REMATCH) trial was published in 2001 and opened the era of DT in patients withend-stage HF not eligible for a heart transplantLike we said, the first-generation VADs sought to create natural circulation by producingpulsatile flow. The setup of the pneumatic chamber, driveline, controller and powersource was relatively big and noisy.Second and third-generation pumps are focused on size, biocompatibility, durability,effectiveness and infection issues. Miniaturization and improved efficiency were themain drivers of developments. The new devices were more reliable with a reduced failurerate.. Patients with this continuous-flow device demonstrateddramatically improved survival compared with patients on first-generation pulsatile flowdevices.The most important second-generation VAD, the redesigned HeartMate II , proved successful as a BTT device in a prospective multicenter study publishedin 2007. Patients with end-stage HF improved after implantation of this device in termsof functional status and quality of life. The FDA approved the HeartMate II as a BTT in2008 and a DT in 2010. Clinical results after implantation of the HeartMate II improvedsteadily to 85% 1-year survival reported 86% 1-year survival after HVADimplantation, with significant improvement in functional capacity and quality of life.Based on this BTT evaluation, the HVAD(r) received FDA approval in 2012.Third-generation LVADs generate continuous blood flow through a centrifugal pump design.The first relevant third-generation LVAD is the HeartWare Ventricular Assist Device(HVAD(r)) , which allows intrapericardial and lessinvasive implantation. The ADVANCE (HeartWare Left Ventricular Assist Device for theTreatment of Advanced Heart Failure) trial. This complication is probably restrainedby the design of the pump, which is characterized by the relatively large housing of theimpeller and by the intermittent creation of at least some 'pulsatility' by theautomated rotational speed variation. The implantation techniques for thethird-generation centrifugal CF pumps preserve the pericardial integrity. Whether thisadvance will help prevent short-term and long-term right HF is still unknown.The HeartMate III is the latest third-generation LVAD, a centrifugal continuous-flow LVADwith a fully magnetically levitated impeller. The MOMENTUM 3  study compared the HeartMate III with the axial flow pump HeartMate II; thefollow-up data are promising. The important finding was that none of the patients withHeartMate III experienced a pump thrombosisRIGHT VENTRICULAR FAILURE is a major factor for the mortality rate among patientswith an LVAD, particularly in patients who are at Intermacs levels 1 and 2 at thetime of implantation. The risk of death after LVAD implantation due to RV failure ishighest in the early postoperative period. Late-onset right ventricular failurecontributes to morbidity and mortality after initially successful LVADimplantation.PUMP THROMBOSIS is a serious complication requiring either surgical pump exchange orsystemic thrombolysis. Although each of these options is technically feasible, eachone results in a large reduction in the 1-year survival rate compared to that with aprimary implant. The obvious increase in LVAD thrombosis may be explained by thesignificantly longer support duration with centrifugal devices. Adherence tostandard anticoagulation recommendations can result in a reduction in the risk ofpump thrombosis.BLEEDING COMPLICATIONS, mainly gastrointestinal, are a great risk of death after VADimplantation. The occurrence of major bleeding may approximate 23%, with arecurrence of nearly 10%. It remains a question if and how the long-term continuousflow contributed to the development of arteriovenous malformations and bleedingevents.DEVICE-RELATED INFECTIONS remain a common cause of morbidity and mortality inpatients with VADs. Transcutaneous drivelines obviously facilitate ascendingstaphylococci-dominated infections. The incidence of device infections variesbetween 13% and 80%. There is data today supporting the decrease of thiscomplication with recent devices.NEUROLOGICAL COMPLICATIONS represents the most devastating risk of death in the mid-to long-term after LVAD implantation. This risk stays constant throughout the first4 years after LVAD implantation. Previous cerebrovascular accident, hyponatremia,low albumin levels, elevated right atrial pressure, enlarged right ventricularend-diastolic dimensions, atrial fibrillation, postoperative infection andsupratherapeutic anticoagulation levels correlate with the incidence ofcerebrovascular accident.DEVICE MALFUNCTION 50% of patients with a VAD experience device malfunctions otherthan pump thrombosis within 1 year postoperatively. The durability and functionalityof LVADs are influenced by numerous factors, including implantation technique,anatomical constraints and complications such as infection and bleeding,anticoagulation, pump settings and device design. Centrifugal pump devices havedemonstrated improved durability compared with pulsatile devices in studies with upto 24 months of follow-up.Transcutaneous energy transfer system and better biocompatibility could probably bethe most important factors in the near future for VADs. This kind of advances willbe capable of yielding better quality of life with reduced risk of complications forthis population of patients.


Tissue Doppler measurements included early (E’) and late (A’) diastolic and systolic (S’) velocity at the mitral and septal annulus of the left ventricle. Measured values were normalized to z-scores using published reference data. Predictors of E’/A’, E/E’, S’ and left ventricular mass index (LVMI) were assessed by multiple linear regression analyses. Tissue Doppler E’ was reduced and tissue Doppler A’ increased, resulting in a reduced tissue Doppler E’/A’ ratio  indicating reduced diastolic function compared to healthy children. Reduced tissue Doppler E’/A’ Z-Scores were independently associated with lower eGFR (p = 0.002) and increased systolic blood pressure (p = 0.02). While E/E’ Z-Scores were increased , patients treated with pharmacological RAS blockade but not with other antihypertensive treatments had significantly lower E/E’ and higher E’/A’ Z-Scores. Systolic tissue Doppler velocities were significantly decreased  and inversely correlated with E/E’ Z-Scores . LVMI was not associated with systolic or diastolic tissue Doppler velocities. Concentric left ventricular hypertrophy showed a tendency to lower S’ in multivariate analysis (p = 0.13) but no association to diastolic function. Concentric left ventricular geometry was significantly associated with lower midwall fractional shortening. In summary, systolic and diastolic function assessed by tissue Doppler is impaired. eGFR, systolic blood pressure and the type of antihypertensive medications are significant predictors of diastolic function in children with CKD. Left ventricular morphology is largely independent of tissue Doppler velocities. Tissue Doppler velocities provide sensitive information about early left ventricular dysfunction in this population.Children with chronic kidney disease suffer from excessive cardiovascular mortality and early alterations of the cardiovascular system. Tissue doppler imaging is a validated echocardiographic tool to assess early systolic and diastolic cardiac dysfunction. We hypothesized that tissue Doppler velocities would reveal reduced cardiac function in children with chronic kidney disease compared to healthy children. A standardized echocardiographic exam was performed in 128 patients of the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) Study aged 6–17 years with an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m Children with CKD are the population with the highest risk for cardiovascular disease. Alterations of the cardiovascular system can be identified at an early age in pediatric populations2.Chronic kidney disease (CKD) is associated with type 4 cardiorenal syndrome and an excessive mortality from cardiovascular disease (CVD). The rate of fatal cardiac events is highly increased in children on dialysis or after kidney transplantation compared to the general population and is the leading cause of death in this patient population3. Likewise in children with CKD, subclinical systolic dysfunction has been described using sophisticated echocardiographic measurements such as strain analysis and endocardial and midwall fractional shortening, while ejection fraction is usually normal5. These findings add to conventional echocardiographic studies with distinct changes in cardiac morphology and geometry in children with CKD7. Tissue Doppler measurements are a reasonable echocardiographic tool in pediatrics since they are non-invasive, hardly time-consuming, widely available and software independent compared to other measurements. The measurement of diastolic indices by Tissue doppler is of particular interest since diastolic dysfunction is regarded as the main abnormality in heart failure with preserved ejection fraction and in adults it is predictive of progress to overt heart failure8. Diastolic dysfunction has also been described as an integral part of cardiorenal syndrome type 4, which is increasingly diagnosed in adults with CKD and is associated with increased mortality rates up to an odds ratio of 4.4 for an eGFR of 40 ml/min/1.73 m2 10. Accordingly, the use of tissue Doppler imaging for evaluation of both diastolic and systolic function has been recommended by the American Society of Echocardiography and the European Society of Cardiology12.Non-invasive exercise tests have shown impaired cardiac performance indices in asymptomatic adult pre-dialysis CKD patientsTissue Doppler measurements include both diastolic and systolic measurements . Derived measures are the E’/A’ ratio describing diastolic function and conventional E to tissue Doppler E’ ratio (E/E’ ratio), a surrogate of left ventricular filling pressure.16. Since pediatric reference values have been provided, quantification of abnormal states across the pediatric age range is readily possible17.Few tissue Doppler studies, in small cohorts, have been conducted to date to evaluate both myocardial diastolic or systolic function in pediatric kidney diseaseThe present study aimed to describe diastolic and systolic function by tissue Doppler parameters in a large cohort of children with CKD and to identify factors associated with impaired systolic or diastolic function.The characteristics of the 128 patients are shown in Table 17  ratio over the mitral valve was not different among CKD groups Table . Tissue 17 Table , Fig. 1.E/E’ Z-Score, a surrogate for left ventricular filling pressure was significantly elevated both at the mitral and septal annulus Table , Fig. 1.Systolic tissue Doppler velocity Z-Scores were again mostly within normal ranges, however significantly reduced at the septal but not at the mitral annulus Table , Fig. 1 Conventional echocardiographic analysis showed elevated LVMI and a high prevalence of LVH, which increased with declining renal function and was highest in dialysis patients Table . RelativLVMI increased with age, was negatively associated with height and higher in male patients. It was associated with systolic function expressed by midwall fractional shortening in univariate and multivariate analysis but not with Doppler velocity Z-Scores or systolic BP SDS Tables  and S4. 17. We demonstrate a significant reduction of systolic and diastolic function in children with CKD compared to healthy children. A critical impact of renal function and blood pressure on diastolic function and a significant association of antihypertensive treatment with RAS blockade with improved left ventricular filling pressure (E/E’ Z-Score) and diastolic function (E’/A’ Z-Score) was evident. In turn, systolic function (S’ Z-Score) was positively influenced by reduced left ventricular filling pressure.This study in a large cohort of children and adolescents with CKD provides novel information about systolic and diastolic left ventricular function in this condition. Our study encompassed a comprehensive analysis of tissue Doppler derived indicators of diastolic function  and systolic function (S’). Measurements were normalized to age-independent z-scoresSmaller studies have obtained tissue Doppler measurements in children with CKD, but their interpretation of the results was usually based on small control cohorts of healthy children. Z-Scores based on published reference data have not been calculated. We therefore demonstrated that available normal data can and should be used to calculate valid Z-scores to interpret tissue Doppler measurements in children.19, there was no significant association of diastolic function assessed by tissue Doppler imaging to left ventricular mass or geometry and only a borderline association of systolic TD velocity (S’ Z-Score) to LV hypertrophy. Midwall fractional shortening was the only functional measure associated to concentric left ventricular morphology. Previous studies have linked E/E’ to left ventricular hypertrophy, but only if LVH was considered very pronounced (>97.5th percentile)18 and in a smaller analysis unadjusted for age20. However, in the presence of LVH, diastolic or systolic dysfunction may play an additional predictive role for future adverse events21 or outcomes, as longitudinal analysis may reveal. More importantly, these results suggest that LV morphology alone does not sufficiently identify risk factors for cardiac involvement in children with CKD nor does it precisely enough describe cardiac alterations.While there was a high prevalence of LVH typical of many CKD and dialysis cohorts16, E’/A’14 or conventional pulse wave Doppler E/A22 were found to be reduced. While an association of diastolic function to serum Cystatin C levels has been shown23, no relationship to eGFR has been demonstrated. Our study, investigating a much larger patient cohort, is the first to show independent associations of both lower GFR and higher blood pressure with reduced diastolic function measured by TDI E’/A’ Z-Score. Additionally, diastolic function measured by E’/A’ Z-Score tended to be better preserved in patients treated with RAS blockade independently of renal function and blood pressure.In previous small-sample studies in children with CKD variable Doppler indices such as tissue Doppler E’24, however its role in childhood is not clear. Here, we observed a globally increased E/E’ Z-Scores, indicative of increased left ventricular filling pressure. In hypertensive adults and children with hypertrophic cardiomyopathy, E/E’ ratio emerged as a powerful predictor of cardiac events25. Also, the finding of the inverse correlation of E/E’ Z-Score with systolic TD velocitiy Z-Score may be of importance since our group previously described abnormal systolic mechanics in children with CKD similar to alterations in hypertrophic cardiomyopathy5.The Heart Failure and Echocardiography Associations of the European Society of Cardiology have recommended the evaluation of E/E’ in the workup of diastolic heart failure in adults26. We therefore hypothesize that RAS blockade should be the preferred treatment for hypertension in children with CKD independent of the level of proteinuria.We describe for the first time an independent association of RAS inhibition with better preservation of LV diastolic function in children with CKD. Notably, the association appeared to be specific for RAS blockers whereas the use of other antihypertensive agents, including diuretics, did not show any relationship with E/E’ Z-Score. Previous studies in pediatric CKD failed to show associations of LV filling pressure (E/E’) with antihypertensive treatment protocols, possibly due to insufficient sample size or lacking adjustment of Doppler measurements for patient ageOur study is also the first to demonstrate a close inverse relationship of E/E’ Z-Score with systolic function in children with CKD. This pathophysiological relationship emphasizes the importance of optimizing diastolic function, preferably by RAS inhibition although other aspects such as the fluid status of patients should not be neglected in order to improve diastolic function.4, TD26, and strain imaging5. Our analysis thus endorses the use of tissue Doppler imaging as a simple method to screen for subtle systolic dysfunction in the setting of normal left ventricular ejection.Furthermore, our results show a reduction not only of diastolic but also of systolic tissue Doppler velocities in children with CKD compared to healthy individuals, suggesting reduced systolic LV function. This finding confirms earlier findings obtained in pediatric CKD cohorts with various methodologies including analysis of fractional shortening29, acute preload changes can impact also on tissue Doppler measurements30. In this study fluid status was not assessed directly. However, none of our patients was in a critically ill condition with acute volume changes, and patients on hemodialysis were examined between dialysis sessions in order to minimize the effects of acute volume changes. Future studies should however look more closely into the effect of fluid status on cardiac function in children with CKD.While tissue Doppler imaging of the left ventricle is supposed to be more independent of preload than flow DopplerAnother obvious limitation of our study is the cross-sectional design of our analysis, which precludes any firm conclusions about causalities.et al. emphasized that the finding of subclinically decreased cardiac function in adults with CKD requires more research into functional mechanisms of cardiac disease in CKD3. Similarly, the Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT) has recently called for more trials evaluating the benefits and risks of cardiovascular medications in patients with CKD31. The observations made in this study underscore the presence of functional myocardial alterations and both the need and feasibility of using non-invasive imaging in interventional clinical trials in the pediatric subset of the CKD population.Chinappa In conclusion, we demonstrated that TD velocities are independent of LV mass and morphology and provide sensitive additional information about early alterations of the left ventricular function in children with CKD. These changes are independently related to the degree of renal functional impairment and systolic blood pressure. Treatment with RAS blockade may be beneficial not only for the prevention of CKD progression but also for cardiac sequelae.32. The study prospectively observes 688 patients who were enrolled 2010–2012 at age 6 to 17 years with CKD stage III-V (eGFR < 60 ml/min/1.73 m2). The patients are followed prospectively with annual comprehensive cardiovascular assessments (including oscillometric BP measurements as previously described2 and echocardiographies) and 6-monthly clinical assessments, blood and urine collection. The measurement of Tissue doppler velocities was not part of the standard echocardiography protocol of the 4C study but was carried out as an ancillary measurement and therefore only available in a subset of patients who were seen by one investigator (A.D.). The patients were not selected specifically for this analysis but were included randomly due to their assignment to the performing investigator. The first available echocardiography per patient during the course of the study was included in the analysis.The patients were participants of the 4C Study  and Institutional Review Boards (IRB) approved the 4C Study: Austria: EC of the University of Vienna; EC of the University of Innsbruck. Czech Republic: EC of the University of Prague. France: Comité de protection des personnes “Est IV”, Strasbourg. Germany: EC Charité— Universitätsmedizin Berlin; EC of the Medical Faculty of the University of Cologne; Ethikkommission der sächsischen Länderkammer; EC of Friedrich-Alexander-University Erlangen; EC of the University of Duisburg-Essen; EC of Albert-Ludwig University Freiburg; Ethikkommission der Ärztekammer Hamburg; EC and IRB of Hannover Medical School; EC and IRB of the University of Heidelberg; EC of the Medical Faculty of the University of Jena; EC of the Medical Faculty of the University of Leipzig; EC of Philipps University Marburg; Ethikkommission der Ärztekammer Westfalen-Lippe und der Medizinischen Fakultät der Westfälischen Wilhelms Universität Münster; EC of the Medical Faculty of the University of Rostock. Italy: Comitato Etico Indipendente dell’Azienda Ospedaliero-Universitaria di Bologna, Policlinico S. Orsola-Malpighi; Comitato di Etica dell’IRCCS Istituto Giannina Gaslini di Genova; Comitato Etico dell’IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena di Milano; Ethical Committee for clinical practice of the General Hospital-University of Padova; Comitato Etico per la Sperimentazione Clinica dell’IRCCS Ospedale Pediatrico Bambino Gesu’ di Roma. Lith- uania: EC and IRB of Vilnius University. Poland: EC at Children’s Memorial Health Institute, Warsaw. Portugal: EC of the University of Porto. Serbia: EC of the University of Belgrade. Switzerland: EC of the Canton Bern; EC of the Canton Zurich. Turkey: EC of the University of Cukurova, Adana; Non-interventional Clinical Researches Ethics Boards of Hacettepe Univer- sity, Ankara; EC of the University of Cerrahpasa, Istanbul; EC and IRB of the University of Ege, Izmir. United Kingdom: Great Ormond Street Hospital and UCL Institute of Child Health research EC. The study was performed in accordance with the ethical standards of the Declaration of Helsinki of 1964 and its later amendments. Written informed consent was given by the parents and adolescents, and oral assent by younger children.33.For the present analysis 128 patients at 12 study sites underwent a standardized echocardiographic exam including tissue Doppler measurements at the time of the study visit. Clinical information and biospecimens collected at the same study visit were analyzed for the present study. GFR was calculated by the updated Schwartz formula34. Patients on hemodialysis were examined between hemodialysis session in order to avoid acute volume changes. None of the patients was critically ill at the time of the investigation. The echocardiographic exam included standard M-mode images, pulsed Doppler and tissue Doppler echocardiography. The left ventricular mass index (LVMI) was calculated according to a recently published allometric formula providing age independent normalization of left ventricular mass (LVM/(height2.16 + 0.09)). An LVM index 2 16 was considered to identify LVH, representing the 95th percentile35. Endocardial and midwall fractional shortening was calculated as suggested by Lang et al.36. Relative wall thickness was normalized to 10 years of age, using a cut-off of 0.38 as equivalent of the 95th percentile37.The transthoracic echocardiographies were performed according to the pediatric echocardiography standards issued by the American Society of CardiologyTissue Doppler measurements included early (E’) and late (A’) diastolic and systolic (S’) velocity at the mitral and septal annulus of the left ventricle. Diastolic function was described by E’/A’ ratio and left ventricular filling pressure by E/E’ ratio.All exams were performed by a single trained paediatrician (A.D.) and reviewed by an expert paediatric cardiologist (M.C.). All exams were performed on an Acuson P50, Siemens Healthcare, Erlangen. Image analysis was carried out using Syngo  as digital image evaluation software.17. Standardized height and BMI were calculated from the WHO growth charts (http://www.who.int/growthref/en). Blood pressure values were standardized according to the Fourth Report on Diagnosis, Evaluation and Treatment of High Blood Pressure in Children and Adolescents38.Results of Tissue Doppler Imaging (TDI) measurements were normalized to patient age by calculation of Z scores based on a published reference cohort of 325 healthy childrenData was tested for normal distribution by the Shapiro-Wilk test. Correlations of all variables of Table Impaired Systolic and Diastolic Left Ventricular Function in Children with Chronic Kidney Disease - Results from the 4C Study, Supplemental Material


Ex-vivo high resolution autoradiographic imaging was conducted to identify accurate ventricular distribution of 18F-LMI1195. In healthy rabbits, 18F-LMI1195 was administered followed by the reference perfusion marker 201Tl for a dual-radiotracer analysis. After 20 min of 18F-LMI1195 distribution time, the rabbits were euthanized, the hearts were extracted, frozen, and cut into 20-μm short axis slices. Subsequently, the short axis sections were exposed to a phosphor imaging plate to determine 18F-LMI1195 distribution (exposure for 3 h). After complete 18F decay, sections were re-exposed to determine 201Tl distribution (exposure for 7 days). For quantitative analysis, segmental regions of Interest (ROIs) were divided into four left ventricular (LV) and a right ventricular (RV) segment on mid-ventricular short axis sections. Subendocardial, mid-portion, and subepicardial ROIs were placed on the LV lateral wall. 18F-LMI1195 distribution was almost homogeneous throughout the LV wall without any significant differences in all four LV ROIs . Subepicardial 201Tl uptake was significantly lower compared to the subendocardial portion . This was in contradistinction to the transmural wall profile of 18F-LMI1195 . A slight but significant discrepant transmural radiotracer distribution pattern of 201Tl in comparison to 18F-LMI1195 may be a reflection of physiological sympathetic innervation and perfusion in rabbit hearts.We aimed to determine a detailed regional ventricular distribution pattern of the novel cardiac nerve PET radiotracer  This phenomenon provokes severe damage to cardiac myocytes, mainly by AMP-mediated calcium overload, and is caused by either elevated plasma concentration of NE, an impaired function of the NE transporter , or reduced plasma clearance of NE in the synaptic cleft2. Recent years have witnessed the more expanded use of cardiac SNS-based imaging utilizing such NET ligands for either single photon emission computed tomography (SPECT) or positron emission tomography (PET) technology, which both allow for a thorough evaluation of sympathetic neurotransmission in HF patients9.On a subcellular level, alterations of the myocardial sympathetic nervous system (SNS) in Heart Failure (HF) patients are predominantly driven by cardiac norepinephrine (NE) spillover3. In the last decade, several cardiac PET radiotracers have been demonstrated to precisely reflect sympathetic nerve integrity in a clinical setting: The prospective Prediction of ARrhythmic Events with Positron Emission Tomography (PAREPET) trial showed that the neuronal SNS PET agent 11C-Hydroxyephedrine (11C-HED) identifies HF patients who are at highest risk for sudden cardiac arrest or death10. While 11C-HED has been extensively used to investigate cardiac sympathetic nerve conditions, its high cost and the necessity of staff to prepare such short-half-life radiopharmaceuticals limit its widespread adoption3. This is in contradistinction to 18F-labeled SNS radiotracers, such as 18F-LMI1195, which do not require costly on-site preparation due to the longer half-life of 18F (110 min). Thus, dispatch from central cyclotron facilities, even by commercial vendors, is feasible and such an approach has been proven to be profitable for the most commonly used oncology imaging agent, 2-deoxy-2-18F-fluoro-d-glucose11.Comparable to their physiological counterpart, those radiolabeled analogs of NE share similar pathways and are also taken up by the uptake-1 mechanism, which clears exocitotically released NE from the synaptic cleft18F-LMI1195 demonstrated superior kinetics compared to 11C-HED, in particular for early imaging time-points. Thus, a phase-3 trial in ischemic cardiomyopathy patients scheduled to receive an implantable cardioverter defibrillator (ICD) is underway and may further corroborate the potential benefit of 18F-LMI1195 for risk stratification12. However, if this PET agent will one day be routinely available in the clinic to help identify high-risk patients and support clinical decision-making, a more precise understanding of the subcellular radiotracer handling may be fundamentally necessary for the interpretation of imaging results. Notably, previous studies have already proven the high affinity of 18F-LMI1195 towards neuronal uptake-1 along with a stable storage in presynaptic vesicles14. However, further insights into the normal regional ventricular distribution of such radiotracers are essential for designing clinical protocols and comprehension of imaging findings. Thus, in the present study, we aimed to elucidate the distribution pattern of 18F-LMI1195 over the left ventricular (LV) wall in healthy rabbits.Moreover, in a recently published phase-2 study, 15.Animal protocols were approved by the local Animal Care and Use Committee  and conducted according to the Guide for the Care and Use of Laboratory Animals 18F-LMI1195 was synthesized following described procedures17. Analyses at the end of syntheses revealed specific radioactivity greater than 100 GBq/μmol and radiochemical purity greater than 95% for the radiolabeled compound.ex-vivo high resolution autoradiographic imaging was conducted to determine accurate ventricular distribution of 18F-LMI1195. As a reference, the myocardial perfusion marker 201Tl was co-injected for dual-tracer analysis. 18F-LMI1195 (25 MBq) was injected via ear vein followed by 201Tl (0.5 MBq). Rabbits were euthanized 20 min after 18F-LMI1195 administration, and the heart was removed. The heart was sliced into 20 μm thickness slices for autoradiographic analysis. The short axis sections were exposed to a phosphor imaging plate  to determine 18F-LMI1195 distribution (exposure for 3 h) with a digital autoradiography system . After complete 18F decay of 3 days, sections were again re-exposed to determine 201Tl distribution (second exposure for 7 d). Figure In healthy New Zealand White rabbits weighing 3.8–4.2 kg (n = 4), 18.In order to quantify radiotracer uptake distribution, regions of interest (ROIs) were drawn on four left ventricular (LV) segments and a right ventricular (RV) segment on a mid-ventricular short axis section. To assess the transmural pattern of radiotracer distribution in the ventricular wall, the ROIs were divided into subepicardial, mid-portion, and subendocardial wall portions on the slicesResults are presented as means ± standard deviation (SD). The two-tailed paired Student’s t-test was used to compare differences between two dependent groups and the two-tailed independent Student’s t-test between independent groups. Values of p < 0.05 were considered statistically significant.18F-LMI1195 distribution was homogeneous throughout the LV wall and no significant differences in radiotracer activity were detected in all short axis LV ROIs .201Tl uptake in the subepicardial portion was significantly lower than in the subendocardial portion . Those findings were in contradistinction to the cardiac SNS radiotracer: 18F-LMI1195 demonstrated no significant differences between the three portions . Representative cross-sectional short-axis images at a midventricular level on dual-radiotracer autoradiography with 18F-LMI1195 and 201Tl are displayed in Fig. 18F-LMI1195 and 201Tl are highlighted in a transmural wall line profile , a slight but significant discrepant transmural radiotracer distribution pattern of the perfusion agent in comparison to 18F-LMI1195 was noted: 201Tl uptake in the subepicardial section was significantly lower than subendocardial, while the SNS agent demonstrated no significant differences over all three wall portions.The present study investigated the transmural distribution pattern of the novel SNS imaging agent 11C-HED serves as a strong outcome predictor for sudden cardiac arrest or death in high-risk HF patients10. However, owing to their short half-life, such 11C-labeled radiotracers suffer from several drawbacks. These include, but are not limited to a potential cold-mass effect (decrease of NE re-uptake function at higher amount of cold mass), the need for a costly on-site cyclotron, and the necessity for expert staff to prepare such radiopharmaceuticals4. Thus, novel 18F-labeled radiotracers for mapping cardiac nerve integrity, such as 18F-LMI1195, may overcome these hurdles: their longer half-life may allow for radiotracer distribution from central cyclotron facilities and flexibility in study design, e.g., by facilitating delayed imaging protocols7.The prospective PAREPET trial demonstrated that denervated myocardium assessed by 18F-LMI1195 for neuronal uptake-1 including cell-membrane binding assays and in vitro blocking studies with the potent uptake-1 blocker desipramine14. In addition, a desipramine chase protocol (delivery after radiotracer injection) led to no increased radiotracer washout, which indicates stable storage in presynaptic nerve terminals. Those findings were further confirmed in NE-expressing, vesicle-poor and vesicle-rich cell lines as well as in an isolated perfused rabbit heart setup using electric field stimulation (as vesicle turnover stimulant)19. Altogether, 18F-LMI1195 is taken up via uptake-1 and stably stored inside presynaptic vesicles and thus, this catecholamine analogue closely mimicks physiological NE turnover. Adding to those previous described findings, the present study provides further insight into the ventricular distribution of 18F-LMI1195 over the LV wall: ex vivo high resolution autoradiographic imaging demonstrated not only homogeneous radiotracer distribution in the LV, but also no significant differences in subendocardial, mid-portion, and subepicardial activity. Thus, the transmural wall line profile of 18F-LMI1195 further corroborates a precise reflection of cardiac sympathetic neurotransmission with this radiotracer. Notably, all of those previously mentioned studies investigating 18F-LMI1195 in a preclinical setting have been conducted using rabbit myocardium: similar to the human heart, NE clearance through neuronal uptake-1 is also pronounced in the rabbit heart. While extrapolations from animals to humans have to be made with caution, the rabbit myocardium may provide a reliable platform to investigate 18F-LMI1195 radiotracer distribution, as it closely mimicks human cardiac nerve integrity20. The findings in this study may, therefore, have direct applicability to the clinical setting.An extensive body of evidence has reported on the high affinity of 201TI and 11C-HED, a larger defect for the latter radiotracer was noted and such uptake defect areas corresponded to the histologically identified regions of denervation. In addition, partial re-innervation in the chronic phase was demonstrated , while no such findings were observed for 201TI18. Further adding to the complexity of this phenomenon, post-infarction sympathetic neuronal damage in humans assessed by 123I-metaiodobenzylguanidine (123I-mIBG) also exceeded the infarct size (assessed by 99mTc-sestamibi SPECT)21. In a prospective setting, Nishisato et al. enrolled 160 patients with consecutive ICDs and compared the myocardial SNS conditions using 123I-mIBG to myocardial perfusion alterations with 99mTc-tetrofosmin. This constituted a combined assessment of cardiac nerve and perfusion status and was of superior benefit in predicting ICD discharge rate than one imaging test alone22. Estorch et al. reported that in patients who developed angina during exercise test, the area of denervated but perfused myocardium was significantly larger than in subjects without angina23. Matsunari and coworkers reported similar findings: Sympathetic neuronal damage measured by 123I-mIBG was larger than the infarct size assessed by perfusion imaging, suggesting higher susceptibility of sympathetic neurons compared to cardiac myocytes21. Integrating those available data, the precise assessment of the transmural wall line profile of different cardiac nerve radiotracers compared to perfusion references in both healthy and impaired myocardium are of value. Thus, if a more widespread adoption of such dual-radiotracer approaches is to be pursued in a clinical setting in the near future, the properties of 18F-LMI1195 described in this manuscript may be of importance for interpreting imaging results of perfusion status and cardiac neurotransmission in the failing heart. In the present study, no in vivo PET study has been carried out. However, previous investigations have already proven the feasibility of in-vivo18F-LMI1195 PET imaging using the identical animal model of New Zeland Rabbits and in humans17. Apart from that, the herein obtained results may lay the groundwork to study both cardiac nerve integrity and myocardial perfusion in dedicated animal models of myocardial ischemia, preferably by using an 18F-labeled SNS imaging agent like LMI1195.In a transient myocardial ischemia model using Wistar rats, a higher susceptibility of cardiac sympathetic neurons compared to cardiomyocytes was demonstrated: in a head-to-head comparison of 201Tl in comparison to 18F-LMI1195 may be a reflection of physiological cardiac sympathetic innervation and perfusion. If 18F-LMI1195 will one day be routinely available in the clinic, the herein presented distinct characteristics in the LV distribution pattern of perfusion status and cardiac nerve integrity may lay the groundwork for a more thorough evaluation of imaging results.In healthy rabbits, a significant discrepant transmural radiotracer distribution pattern of


To detect the responsiveness and predictive ability of the Chinese version Action Research Arm Test (C-ARAT) in participants within the first 3 months after cerebral infarction.  Ninety-seven individuals  with a first cerebral infarction were enrolled in this study. The participants were evaluated by two outcome measures: C-ARAT and the Barthel Activities of Daily Living Index (BI) at five time points: 0D, 3W, 3M, 6M and 1Y after enrolment. The standardised response mean (SRM) and the Wilcoxon signed rank test were used to analyse responsiveness. Predictive validity was determined by using Spearman's rank correlation coefficients. The predicted performance of C-ARAT on activities of daily living (ADLs) was measured by linear regression model. Floor and ceiling effects were estimated by counting the proportion of subjects falling outside the 5% lower or upper boundary, respectively. ρ = 0.561–0.624, p < 0.001), and exhibited fair correlation with the BI score 1Y after enrolment . C-ARAT was a good predictor (adjusted R2 = 0.185–0.249) of BI within 3M follow-up. The C-ARAT total score showed a notable floor effect at 0D and 3W and a notable ceiling effect at 3M, 6M and 1Y.  The C-ARAT showed moderate to large responsiveness in detecting changes over time (SRM = 0.58–0.84). The C-ARAT subscales showed small to large responsiveness (SRM = 0.44–0.90). The C-ARAT at 0D showed moderate to good correlation with the BI scores at 3W, 3M and 6M ( The results of this study support the use of the C-ARAT as a measurement of upper extremity function in individuals with a first cerebral infarction. Stroke is a leading cause of adult disability across the globe . Stroke Several measures are used in the clinic for assessing UE impairment or disability –13. One To further examine the psychometric properties of the C-ARAT, the aim of this study was to detect the responsiveness, predictive ability for ADLs and floor and ceiling effects of the C-ARAT in people with early cerebral infarction.The original ARAT and its manual were translated from English to Chinese using a forward-backward procedure by an expert group. The translation protocol was published in a previous article .The subjects for this study, recruited by a convenience sampling method, were inpatients in the Department of Rehabilitation Medicine, the First Affiliated Hospital of Sun Yat-sen University, China, from August 2014 to December 2018. The inclusion criteria were as follows: (1) the occurrence of a first cerebral infarction with unilateral hemiparetic lesions confirmed by magnetic resonance imaging or computed tomography; (2) an interval of <3 months after cerebral infarction; (3) age of 40–80 years; (4) ability to maintain a sitting position for >30 min; (5) no severe deficits in communication, memory and understanding; (6) no additional medical, cardiovascular or orthopaedic condition or significant UE peripheral neuropathy; (7) willingness to participate in this study and sign the informed consent.The participants' demographic details and major comorbidity data were collected from medical records.This study was approved by the Human Subjects Ethics Subcommittee of the First Affiliated Hospital, Sun Yat-sen University, China. Informed written consent was obtained from all of the participants.Prior to baseline data collection, an experienced physiotherapist with 9 years of clinical experience in stroke rehabilitation was trained to properly administer the C-ARAT and the Barthel ADLs Index (BI). The C-ARAT and BI were administered at five time points: the first day of hospitalisation and enrolment (0D), 3 weeks after enrolment (3W), 3 months after enrolment (3M), 6 months after enrolment (6M) and 1 year after enrolment (1Y). The scores of the C-ARAT measured at 0D, 3W, 3M, 6M and 1Y were used to analyse the responsiveness and floor and ceiling effects. The BI scores at 3W, 3M, 6M and 1Y were used as the criteria for examining the predictive ability of the C-ARAT measured at 0D. The outcome measures were conducted in a random order by lucky draw in a quiet room. During the evaluation, participants could take sufficient rest to avoid the influence of fatigue caused by the assessment. Thus, the entire assessment took approximately 20–30 minutes.ρ = 0.73–0.97) [The ARAT is a performance test for evaluating arm and hand function and dexterity after stroke . Many st73–0.97) , 23, 24 73–0.97) –21 effic73–0.97)  presente73–0.97) . The C-A73–0.97) . UE funcρ ≥ 0.92; inter- and intra-reliability, intra-class correlation coefficient ≥0.83) [The BI is a measure of ability in basic ADLs . The relt ≥0.83) , 27. Pret ≥0.83) , 29. Furt ≥0.83) . It was p value <0.05.All of the statistical analyses were performed using SPSS version 20.0. All of the tests applied were two-tailed. The level of significance was set at a n = 97) were demonstrated by descriptive statistics. The distribution of all the data was subjected to the Shapiro-Wilk test.Demographic and clinical characteristics of participants of this study  were used to calculate the correlation between C-ARAT on 0D and BI at all the follow-up time points as appropriate. The ρ values between 0 and 0.25 were considered low; ρ values between 0.25 and 0.50 were considered fair; ρ values between 0.50 and 0.75 were considered moderate to good; and ρ values >0.75 were considered good to excellent correlations [Predictive validity was used to detect whether the total and each subscale in the C-ARAT was significantly correlated with certain future criterion measures . Pearsonelations . If therelations .p > 0.05).Ninety-seven individuals with a first cerebral infarction were enrolled in this study. Of the 97 subjects who met the inclusion criteria and began to participate in the study, 6 individuals were lost to follow-up at 3 weeks after enrolment. There were 38 individuals who could not return to the hospital because of transportation difficulties at 3 months, 55 at 6 months and 62 at 1 year after enrolment. Thirty-five participants completed all of the assessments. ρ value from 0.521 to 0.624 (p < 0.001), except for the pinch  and grip (with the BI score at 6M) subscale scores with a fair correlation with ρ value = 0.440–0.497 (p < 0.01). The C-ARAT total and subscale scores at 0D had fair correlation with the BI score at 1Y, with ρ value from 0.260 to 0.390 . The C-ARAT and subscales at 0D showed good predictive ability on BI scores at 3W and 3M with adjusted R2 value from 0.111 to 0.290 (p < 0.01). The C-ARAT and subscales at 0D was not a significant predictor on BI scores at 6M and 1Y with adjusted R2 value from 0.005 to 0.082 (p > 0.05), except that the grip and gross-movement subscale scores at 0D showed good predictive ability on BI scores at 6M with adjusted R2 value from 0.071 to 0.109 (p < 0.05). The C-ARAT showed the best predictive ability with the BI score at 3W and showed the lowest predictive ability with the BI score at 1Y. Among the total and subscale scores, the pinch subscale showed the lowest predictive ability, and the gross-movement subscale showed the highest predictive ability.This was the first study to explore the responsiveness, predictive validity and floor and ceiling effects of the C-ARAT in people with a first early cerebral infarction. Our results demonstrate that the C-ARAT had moderate to large responsiveness. The C-ARAT had moderate to good correlation with the BI score at 3W, 3M and 6M and had fair correlation with the BI score at 1Y. C-ARAT was a good predictor of BI score within 3M follow-up but not 6M and 1Y follow-up. The C-ARAT showed a notable floor effect at 0D and 3W follow-up and a notable ceiling effect at 3M, 6M and 1Y follow-up.Our results demonstrated that the C-ARAT total score showed a notable floor effect at 0D and 3W follow-up, indicating a poor functional UE in most of the participants at admission. Consistent with our results, Hsueh et al.  reportedOur results indicated that the C-ARAT showed notable ceiling effects at the latter three time points . This may to some extent indicate that the participants achieved considerable recovery of their UE function. Similar to our results, Dorothy et al. reported that the ARAT showed a notable ceiling effect at days 14 and 90 after enrolment , and Lind during evaluation of early-stage stroke patients, with effect size d = 0.49–1.390, indicating small to large responsiveness [Our results demonstrated that the C-ARAT had moderate responsiveness in detecting changes at 0D–3W and 0D–3M and large responsiveness at 0D–6M and 0D–1Y in this study sample. Similar to the first two sessions of our study, Rabadi et al. reported that the ARAT showed moderate responsiveness (SRM = 0.68) during evaluation of 104 early-stage (onset: 16 ± 9 days) stroke patients who were studied with two measurements at admission and discharge with a mean stay of 34 ± 15 days . Hsieh esiveness , 35. Thesiveness  reviewedsiveness  suggesteAmong the four subscales, the grip subscale, similar to the total score, had moderate responsiveness within 3M follow-up and large responsiveness after 6M follow-up. The gross-movement subscale had the highest responsiveness during the first three time periods. These observations might indicate that participants mainly achieved gross-movement improvement at the early stage and then mainly regained grip function improvement within 1 year follow-up. The pinch subscale had the lowest responsiveness at each session. This might indicate that the pinch function was the most complicated and difficult to recover.ρ > 0.5) between the ARAT score at 14 days after stroke and the BI score at 180 days after stroke during evaluation of 53 individuals with early stroke (onset within 2 weeks) [Our results showed that the C-ARAT total score showed moderate to good correlation with the BI scores at 3W, 3M and 6M and exhibited fair correlation with the BI score at 1Y after enrolment. In agreement with our results, the study of Lin et al. showed a moderate correlation (2 weeks) . Meanwhi2 weeks)  reported2 weeks) . FIM ass2 weeks) . The lowInterestingly, we found that the C-ARAT may be a good predictor of the level of ADL within 3M follow-up. C-ARAT may be an optimal predictor of ADLs in acute and subacute phases of stroke. Kwakkel found that the severity of upper limb motor impairment at onset of the stroke had some impacts on the probability of regaining the upper limb motor function in the acute phase of stroke . In thisThis study had some limitations. First, the study subjects were selected by convenience sample method. The subjects were recruited from the hospital in their acute phrase of stroke. Most of them showed a strong will towards stroke rehabilitation. This attribute may have led to the over-representation within the sample of particularly active individuals. Second, the sample size was small at the follow-up of 1Y. The conclusion may only apply to the subjects in our study. A larger sample size with different phases of stroke may help us to draw a more generalisable conclusion. Third, enrolment onset was 4–81 days, which was a somewhat large range and might somehow have some impacts on the results. Our study found that C-ARAT can predict BI from acute to subacute stroke. Although all the subjects were recruited in acute phase of cerebral infarction, the registration time after cerebral infarction was various. It may somehow deteriorate the result in our study. In order to minimize the variation in the onset and draw a more reliable conclusion, subjects within 2 weeks post stroke  would beThe C-ARAT showed acceptable levels of responsiveness in people with cerebral infarction. C-ARAT was a good predictor of ADL performance in acute and subacute phases of cerebral infarction. Our results support the use of the C-ARAT as a valid measure of UE impairment in individuals with a first cerebral infarction.