Radionuclide-based imaging is an alternative to evaluate ventricular function and synchrony and may be used as a tool for the identification of patients that could benefit from cardiac resynchronization therapy (CRT). In a previous work, we used Factor Analysis of Dynamic Structures (FADS) to analyze the contribution and spatial distribution of the 3 most significant factors (3-MSF) present in a dynamic series of equilibrium radionuclide angiography images. In this work, a probability density function model of the 3-MSF extracted from FADS for a control group is presented; also an index, based on the likelihood between the control group's contraction model and a sample of normal subjects is proposed. This normality index was compared with those computed for two cardiopathic populations, satisfying the clinical criteria to be considered as candidates for a CRT. The proposed normality index provides a measure, consistent with the phase analysis currently used in clinical environment, sensitive enough to show contraction differences between normal and abnormal groups, which suggests that it can be related to the degree of severity in the ventricular contraction dyssynchrony, and therefore shows promise as a follow-up procedure for patients under CRT. Heart failure (HF) is defined as a complex clinical syndrome that can result from any structural or functional cardiac disorder and that impairs the ability of the ventricle to fill or eject blood . AccordiVentricular dyssynchrony has also been associated with increased mortality in HF patients , 4. DyssThe established criteria to select candidates for CRT are limited.The stimulation leads are not properly placed.There is excessive fibrous tissue at the stimulus location.However, 20% to 30% of patients having HF do not benefit from resynchronization therapy, probably due to several causes .The estaThis has led to the definition of several indexes, extracted from imaging modalities, to measure the cavities mechanical contraction, and that allow the proper identification of candidates to undergo CRT . The quaRadionuclide-based imaging is another alternative to evaluate ventricular contraction synchrony . The equERNA images are processed by adjusting the first harmonic component of the Fourier Transform (FT) of each pixel's temporal intensity evolution (time-activity curve (TAC)). From these components, phase angles, which are representative of the TAC behavior, are extracted and a map (phase image) of the ventricular contraction sequence is constructed . SeveralThe standard deviation of the pixels' phase angles measured in each ventricular Region of Interest (ROI) represents intraventricular dyssynchrony and the difference between the means of the phase angles of both ventricular ROI represents interventricular dyssynchrony . SeveralFactor Analysis of Dynamic Structures (FADS) has also been proposed as a valuable tool to detect abnormalities in ventricular cavities' movement , 32. It In this work, a probability density function model of the 3-MSF, extracted from FADS for a control group, is presented; also a reference normality index, based on the likelihood between the control group's contraction model and a sample of normal subjects, is proposed. The index was then statistically compared with those computed for two populations of patients satisfying the clinical criteria to be considered as candidates for a CRT: a group with complete left bundle branch block (LBBB) and a group with dilated cardiomyopathy (DCM). The paper is structured as follows: in the Methodology section we describe the proposed model to characterize a normal contraction pattern Sections  and 2.2;XTAC = X be a bidimensional array th pixel value of the kth frame of the acquired image series. Each frame size is M × M pixels (p = (i − 1) × M + j, q = k) as shown in XTAC represents the time-series generated for each pixel on the image set, known as time-activity curves (TAC)  .Q be a linear transformation that decorrelates the ERNA image set (XTAC), so thatF are the factors of XTAC  with the mean-value removed; V is the eigenvector set of the autocorrelation matrix of Xm and D is the scaled diagonal matrix of the eigenvalues set of the autocorrelation matrix of Xm. The contribution of each factor is determined by the corresponding eigenvalue magnitude.Let AC , Xm is V.The three most significant factors (3-MSF) of the ERNA studies, obtained for a population of normal subjects, were analyzed; the spatial distribution of those factors can be observed in R Gaussian density functions (Gaussian mixture), defined by the following expression [f is observed variable, wr is relative weight of the rth gaussian function of the mixture, and N is the multivariate Gaussian PDF with μr and Σr parameterswr,   μry Σr} for r = 1,…, R, the expectation maximization algorithm, that maximizes the mixture model likelihood, was used [The probability density function (PDF) of those factors was modeled by a linear combination of pression :(2)p(f)was used .http://www.r-project.org/) [Six data groups were assembled, with 10 subjects each, randomly selected from a total of 23 control subjects, following a standard bootstrap resampling procedure. The PDF of the 3-MSF was modeled for each group, using the procedure described above. The number of components of the Gaussian mixture was determined considering the bayes information criterion (BIC) , 39. Thect.org/) .fs) represents the probability that those observations are well described by the assumed model , in this work we propose a normality index based on this probability. Assuming statistical independence between observations, the average log-likelihood of a sample set with respect to the reference  population can be defined as a comparative index (IN) of a normal contraction pattern as follows:S is the observations' set, that in our case corresponds to the ventricular region TACs for each subject.Considering that the likelihood estimated on a data sample (IN) for a group of eight normal subjects (not considered for the mixture parameters estimation) was measured and statistically compared with the indices obtained for LBBB and DCM subjects.The normality index ; all individuals gave their informed consent to participate in the study. The specific characteristics for these populations are shown in LBBB occurs whenever the electric impulse traveling from auricles to ventricles is interrupted, thus causing a QRS complex duration longer than 0.12 s. This delay provokes interventricular contraction asynchrony which can progress to eventually become cardiac insufficiency . The LBBSubjects with idiopathic DCM and cardiac insufficiency present left ventricle (LV) or right ventricle (RV) dilatation of unknown causes, inter- and intraventricular abnormal contractility; they must reunite all of the criteria to be considered as CRT candidates –44. The The control population consisted of 23 volunteers  having an EF of 60 ± 5.84%; with a low probability of coronary arterial disease and without a history of myocardial acute infarct. This group presented an EKG without abnormality and their cardiac function was considered normal, after a thorough clinical evaluation.General Electric millenium MPR/MPS gamma camera was used for all ERNA image acquisition. It has a single head with 64 photomultiplier tubes and it is equipped with a low energy, high resolution parallel-hole collimator; the calibration of the energy peak was centered at 140 KeV and the detector's uniformity was guaranteed at less than 5% [The same  than 5% . Images in vivo/in vitro modified technique with 740 to 925 MBq of Tc-99m, using an UltraTag Kit [Erythrocytes were marked applying an aTag Kit , 47. EKGFor each subject, an image corresponding to the end of diastole was selected and manually segmented by an expert, to define the ventricular area. This segmentation defines a mask that is used to automatically extract the ventricular regions from the other frames.t-test for independent samples and considering P ≤ 0.01. The SPSS version 10.0 software was used for all statistical analyses.The normality indices are expressed as the mean value ± standard deviation. Indices measured for the normal group were independently compared to those obtained for LBBB and DCM populations, using a To summarize, the methodology is divided in two stages: training to obtain the model's parameters  and applThe information obtained for the 3-MSF  of the left and right ventricular regions was projected into scatter plots to observe differences between populations and between ventricular regions. Figures The scatter plots obtained for the subjects studied show that the information for the left and right ventricles is overlapped in the control population , but alsDifferent models were obtained for the PDF of the 3-MSF for six groups, with 10 subjects each, randomly selected from the control population. w), mean values (μ), and covariance matrices (Σ) that describe the selected model are shown in For the control population, the minimum BIC and log-likelihood values corresponded to model 5, so that it has the highest probability of best describing the data corresponding to the PDF of the F1, F2, F3 distribution of the normal contraction pattern group. This model is characterized by having five Gaussian functions with variable volume, shape, and orientation. The weight parameters  obtained for the populations studied, compared with the defined normal contraction model , are prFor comparison purposes, in Inter- and intraventricular contraction synchrony plays an important role in the heart pump function. The deterioration of contraction homogeneity can lead to a poor prognosis of clinical evolution, while a restoration of the ventricular contraction has proven to be of clinical benefit in patients with heart failure. However, despite the fact that several studies show that CRT can be of great benefit for severe cardiac malfunction, still up to 30% of patients do not recover after therapy. Several attempts have been made to improve patient selection and to foresee the successfulness of cardiac resynchronization therapy, depending on the particular dyssynchrony. In a large study, Chung et al.  concludeAn analysis of the 3-MSF scatter plots obtained for the populations studied indicates that the third factor information is necessary to separate left and right ventricular regions, particularly for the abnormal contraction populations, as can be observed in Figures The comparison of the 3-MSF PDF obtained for the normal population with respect to the behavior of LBBB and DCM groups, using the proposed index, has the advantage of not assuming a specific sequence for the normal contraction pattern and does not depend on the size of the ventricular cavities. It can be observed in Due to the reduced sensitivity and specificity of echocardiographic measures to adequately select CRT candidates, ERNA extracted indices seem more reliable in detecting ventricular dyssynchrony. In this work, the probability density function that models a normal ventricular contraction pattern has been defined and validated for a control population. It is based on a thorough analysis of the three most significant dynamic factors obtained from ERNA images in several populations presenting different patterns of ventricular synchrony. Furthermore, a metric to quantify differences between pathologic populations and the reference normal contraction pattern has been proposed; the validation of this likelihood measure was carried out in patients with complete left bundle branch blockage and dilated cardiomyopathy. Both populations presented statistically significant differences in their contraction pattern, compared to the reference model and these differences were more important for the DCM population, due to inter- and intraventricular dyssynchrony, as expected. Compared to the Fourier phase analysis, and particularly with the standard deviation, the proposed index also detects differences between normal and pathologic groups. Furthermore, this index, together with FADS, was sensitive enough to show contraction pattern differences, which suggests that this analysis can be related to the degree of severity in the ventricular contraction dyssynchrony. Additionally, the use of this index may be promising for the followup of patients under CRT. In future work, other clinical information should be incorporated, either extracted from EKG or from different imaging modalities, to propose an integrated normality index, to enhance patient selection for CRT. Also, longitudinal studies through different stages of treatment will be necessary to validate the index's capacity to measure asynchrony severity, particularly in patients that have been submitted to cardiac resynchronization therapy.


Diffuse myocardial fibrosis (DMF) is an important factor in cardiac disease, but until recently could only be accurately assessed with biopsy. We hypothesised that DMF measured by Equilibrium contrast CMR (EQ-CMR) is elevated in cardiac pressure overload (hypertension and aortic stenosis), that the degree of DMF will track the clinical severity of pressure overload and cardiac effects, and as such DMF may be a key biomarker in assessing the cardiac effects of pressure overload.ECV measurement was by EQ-CMR. The T1 mapping sequence was ShMOLLI. The contrast agent was Gadoterate meglumine (Dotarem) at 0.1mmol/Kg (bolus) plus infusion at 15 minutes at 0.0011 mmol/kg/min. CMR was at 1.5T (Siemens Avanto):ECV = (1-hematocrit)x (1/T1)myo ÷ (1/T1)blood.ECV was measured in 43 patients with isolated, well-controlled hypertension , 28 patients with severe aortic stenosis (AS) undergoing aortic valve replacement , and 50 healthy volunteers .ECV measurements were the lowest in the control group with significantly higher ECV values in hypertension and AS ; end-systolic and diastolic volumes were not significantly different among cohorts.The mass index increased from normal to hypertension to AS (66 g/mThe myocardial ECV increases with the degree of left ventricular pressure overload hypertrophy.British Heart Foundation; National Institute for Health Research.


Amyloidosis (AM) is a disease complex that results from extra-cellular protein deposition of uniquely twisted and insoluble beta pleated sheet fibrils that can be found in several acquired or hereditary AM forms. Clinically apparent cardiac involvement can be seen in about 30% of patients resulting in a restrictive cardiomyopathy, which is the most common cause of death in these patients. Recently, there was compelling evidence that polyphenol epigallo-catechin-3-gallate (EGCG), a chemical component of regular green tea, induces aggregation products that do not polymerize into fibrils. Cardiac MRI is the reference standard for measurement of cardiac function, myocardial mass and cardiac remodeling but has not been used for longitudinal follow-up of AM patients treated with EGCG.We hypothesized that cardiac MRI is able to detect changes in cardiac function, myocardial mass and LV remodeling in AM patients being treated with EGCG for 12 months.In a twelve-month follow-up, we studied 12 patients  with acquired or genetic forms of AM using a whole body 1.5T CMR scanner (Philips Achieva). Vector-ECG gated short axis, two and four chamber cine slices with parallel image acquisition covering the entire left ventricle (LV) were acquired using a regular SSFP sequence. LV volumes and myocardial mass were acquired by manual drawing of endo- and epicardial borders. In a blinded fashion, two observers at different time-points assessed twice left ventricular (LV) end-diastolic and systolic volumes , stroke volume (LVSV), ejection fraction (LVEF) and longitudinal shortening. P<0.05 was considered statistically significant.Results are shown in Table In a small study cohort of AM patients treated with EGCG, our results provide preliminary evidence that after a twelve month period of treatment, myocardial mass was significantly reduced, although myocardial function was primarily unaffected. The molecular mechanisms- whether EGCG can elutriate existing extracellular fibrils or whether it modifies the deficient proteins avoiding the extracellular precipitation- as well as the clinical relevance regarding modified risk stratification, future cardiac events and event-free survival warrant further investigation in a much larger patient cohort.None.


Imaging has played a leading role, including such techniques as contrast echocardiography,2 x‐ray angiography with measurement of myocardial perfusion grade,3 and contrast‐enhanced cardiac magnetic resonance (CMR) imaging.5fter acute reperfused myocardial infarction (AMI), there is a variable degree of microvascular damage due to reperfusion injury. This injury is multifactorial, and potential culprits include cellular inflammation (leukocytes and macrophages), reactive oxygen species, shifts in metabolic substrate, and alterations in mitochondrial and cytosolic calcium ion homeostasis.6 for the left ventricle (LV) over time because of adverse remodeling,7 and for the patient in terms of risk of morbidity and mortality.8 In addition, myocardial hemorrhage has been recognized as another marker of severe injury9 and can be imaged on T2‐weighted MRI as areas of low signal intensity. Yet another marker of prognosis by CMR is myocardial salvage index. Myocardial salvage index is calculated as the difference between the area at risk, identified by T2‐weighted (W) imaging as regions of bright signal consistent with myocardial edema,10 and infarct size, which is measured by late gadolinium enhancement.11 In a recent study of patients followed up for 6 months after AMI, myocardial salvage index was a powerful predictor of outcome, inasmuch as nearly all of the cardiac events occurred in patients with myocardial salvage index less than the median.12Markers of reperfusion injury on CMR include microvascular obstruction, which appears as regions of hypointense signal in the first few minutes after gadolinium contrast administration. CMR studies have demonstrated that microvascular obstruction is associated with poor outcome for the particular segment of myocardium in which it occurs,13 IMR is measured with a pressure sensor / thermistor–tipped guidewire and is calculated as mean distal coronary pressure × mean transit time of a 3‐cc saline bolus measured during adenosine hyperemia. Fearon et al13 demonstrated in 29 patients after primary percutaneous coronary intervention for AMI that IMR correlated significantly with 3‐month post–myocardial infarction echocardiographic wall motion score and was its strongest predictor on multivariate analysis. IMR also predicted recovery of regional LV function.In the past few years, a catheter‐based technique has been developed for assessment of microvascular injury in the setting of AMI—namely, the index of microcirculatory resistance (IMR).Journal of the American Heart Association (JAHA), Payne et al14 studied the use of this technique in a larger cohort (n=108) of post‐AMI patients and compared the results with CMR studies at 2 days after AMI and 3 months after AMI. The authors are to be congratulated on the completion of this tour‐de‐force, which involved a large number of patients and 2 follow‐up imaging studies, for which they had an 89% completion rate. They found that the measurement of IMR was extremely reproducible. IMR was a multivariate predictor of early myocardial salvage and predicted the presence and extent of microvascular obstruction and myocardial hemorrhage. In anterior myocardial infarction, IMR predicted late myocardial salvage. Thus, a catheter‐based measurement in AMI can accurately assess the extent of microvascular injury while percutaneous coronary intervention is being performed, which is a potential way to obviate the need for further imaging of microvascular injury. Still, the correlations with 3‐month ejection fraction and end‐systolic volumes were modest and, in fact, fell out in multivariate models because IMR correlated much better with baseline measures of acute microvascular injury on CMR. This could have been, at least in part, because the infarct sizes were modest and ejection fractions fairly preserved, and thus the subsequent LV remodeling, which is dependent on initial infarct size, was likewise modest.In this issue of the yes, given that measurement of Thrombolysis In Myocardial Infarction (TIMI) grade is an inadequate way of assessing microvascular function. Next, does IMR obviate performance of further imaging, such as CMR to assess the status of the microvasculature? This is a more difficult question to answer. Certainly, IMR adds to the understanding of myocardial physiology after reperfused myocardial infarction. One could ask, even though IMR correlated with the presence and extent of microvascular obstruction and myocardial hemorrhage, “Why not just perform the CMR and get a complete and definitive evaluation?” Certainly, cost and availability are issues with CMR. Not every hospital has CMR capability, and the additive cost of a study is not inconsequential. Payne et al14 contend in the introduction to their article that CMR is “usually performed up to 7 days after hospital admission in medically stabilized patients.” Perhaps that is true in Scotland. In the United States, hospital stays are generally on the order of 2 to 3 days after reperfused myocardial infarction, and thus CMR, if it is to be performed, must be obtained quite early on in the admission. It is safe to perform CMR even in the first 24 hours. Yet another question is, “Why was the correlation with subsequent LV remodeling less strong than the correlation with measures on the CMR at day 2?” What one would really like to have at the time of index evaluation is the ability to predict late outcomes over and above assessment of the current state of the myocardium.Several questions are raised by this interesting study. First, does the IMR measure add to what we already know at the time of intervention? The answer is a decided 15 but further studies have not been performed since that publication. A multitude of other pharmacological agents have fallen by the wayside. Does it make sense to examine the microvasculature after AMI if we have no proven therapy to improve microvascular function and thus change subsequent LV remodeling and outcome? As it stands now, all post‐AMI patients leave the hospital on 5 drugs, including aspirin, a statin, a β‐blocker, an angiotensin‐converting enzyme inhibitor, and clopidogrel—the latter if they received a stent as part of the percutaneous coronary intervention. No adjustments are made on the basis of the status of the microvasculature because these therapies are considered standard‐of‐care, and hospitals are monitored for adherence to this post‐AMI medical regimen. Until such time as we have specific therapies for microvascular injury, it might not make sense to look for it, even though we have accurate ways to assess it with CMR and now IMR. Although the physiology is certainly of great interest, no method of assessing microvascular function after reperfused AMI has reached the current high bar of practicality and clinical utility.The larger question is, “In which patients should microvascular function be assessed after reperfused AMI?” The issue here is that despite exhaustive studies over the past 3 decades, little progress has been made in mitigating reperfusion injury. Intravenous adenosine had some promise in that regard in the Acute Myocardial Infarction study of Adenosine (AMISTAD‐II), in which infarct size was reduced with the higher dose and trends toward benefit were seen in larger anterior infarcts,


Regional myocardial ischemia and late gadolinium enhancement (LGE) defined by cardiac MR imaging are also reported as significant prognosticators for future cardiac events. However, the prognostic value of coronary flow reserve (CFR) obtained by MR flow measurement remains uncertain. The aim of this study was to evaluate the prognostic value of CFR determined by phase contrast cine MR imaging of the coronary sinus in patients with known or suspected coronary artery disease (CAD).Recent studies demonstrated that 203 patients  with known or suspected CAD underwent cardiac MR studies including phase contrast cine MRI of coronary sinus, and stress-rest perfusion and LGE MR imaging. The patients with previous revascularization were excluded from this study. Presence or absence of regional ischemia in ≥2 AHA segments and LGE in any myocardial segment were visually determined on stress-rest perfusion and LGE MRI, respectively. CFR was obtained as the ratio of coronary sinus flow assessed by phase contrast cine MRI at baseline and during ATP stress and categorized in tertile . MACEs were defined as cardiac death, late revascularization (>90days), acute myocardial infarction, unstable angina, heart failure, and ventricular arrhythmia.During a median follow-up period of 12 months , MACEs were observed in 6 (24.0%) of 25 patients with lower CFR tertile, 2 (5.6%) of 36 patients with middle CFR tertile and 6 (4.2%) of 142 patients with upper CFR tertile, corresponding to the annual event rate of 22.7%, 8.2% and 7.2%, respectively. Kaplan-Meier curve demonstrated a significantly lower MACE-free survival rate in patients with lower CFR tertile compared to those with middle and upper CFR tertile  . In a stepwise multivariate Cox model adjusting for age, gender, hypertension, diabetes, hyperlipidemia, smoking, family history of premature CAD, and obesity, the lower CFR tertile , presence of regional ischemia  and presence of LGE  were independent predictors of MACE.CFR quantified by phase contrast cine MR imaging of the coronary sinus can predicts future major cardiac events in patients with known or suspected CAD independent of the conventional cardiac MR predictors such as presence of regional ischemia and infarction.Departmental research funding.


Non-ischemic dilated cardiomyopathy (DCM) is the most common cardiomyopathy worldwide, with significant mortality. Correct evaluation of the patient's myocardial function has important clinical significance in the diagnosis, therapeutic effect assessment and prognosis in non-ischemic DCM patients. This study evaluated the feasibility of three-dimensional speckle tracking imaging (3D-STE) for assessment of the left ventricular myocardial strain in patients with non-ischemic dilated cardiomyopathy (DCM).Apical full-volume images were acquired from 65 patients with non-ischemic DCM (DCM group) and 59 age-matched normal controls (NC group), respectively. The following parameters were measured by 3D-STE: the peak systolic radial strain (RS), circumferential strain (CS), longitudinal strain (LS) of each segment. Then all the parameters were compared between the two groups.P < 0.001 for all). The interobserver, intraobserver and test-retest reliability were acceptable.The peak systolic strain in different planes had certain regularities in normal groups, radial strain (RS) was the largest in the mid region, the smallest in the apical region, while circumferential strain (CS) and longitudinal strain (LS) increased from the basal to the apical region. In contrast, the regularity could not be applied to the DCM group. RS, CS, LS were significantly decreased in DCM group as compared with NC group (3D-STE is a reliable tool for evaluation of left ventricular myocardial strain in patients with non-ischemic DCM, with huge advantage in clinical application. Non-ischemic dilated cardiomyopathy (DCM) is the most common cardiomyopathy worldwide, with significant mortality. In this disorder, dilation and impaired contraction of the left or both ventricles develops . DCM is In recent years, the research on myocardial function in patients with non-ischemic DCM has become a hot topic in cardiovascular ultrasound -6, whichThree-dimensional speckle tracking imaging (3D-STE) technique is a new ultrasonographic method recently developed for noninvasive monitoring of regional and global myocardial function in clinical practice. Compared with the quantitative tissue velocity imaging and two-dimensional speckle tracking imaging, it has great advantages because it is independent of angle and does not ignore the characteristics of three-dimensional cardiac wall motion. Recently, a lot of studies have focused on different pathologic conditions -11, whilSixty-five outpatients and inpatients with non-ischemic DCM were consecutively enrolled in the study from Union Hospital, Wuhan. Eleven patients (16%) were excluded after echocardiographic acquisitions due to either irregular heart rhythm (n = 4) or insufficient image quality (n = 7). The remaining patients , aged from 19 to 65 years old with an average of 48 years old were studied. The diagnosis of non-ischemic DCM was made on the basis of echocardiography (LV dilation and diffuse hypocontractility), electrocardiography (absence of Q waves), clinical criteria , and coronary angiography (no significant coronary artery stenosis). Inclusion criteria included: (1)according with Framingham heart failure diagnostic criteria in 1971, NYHA classification ≥ IIgrade; (2) left ventricular ejection fraction (LVEF) < 50%; (3)LV end-diastolic dimension > 112% of the predicted value, corrected for age and body surface area. Exclusion criteria were presence of rhythms other than sinus rhythms in electrocardiography (ECG), pacemaker implantation, coronary artery disease , valvular heart diseases, and congenital heart diseases.Fifty-nine healthy volunteers were consecutively enrolled as the control group (NC group), and seven subjects (11%) were excluded from this study because of insufficient image quality. The remaining 52 subjects  with no organic disease based on physical examination, electrocardiogram, and echocardiography; and no risk factors for hypertension or coronary heart disease were finally included in the statistical analysis.Each study was assessed for image quality using a four-grade scale based on the adequacy of visualization of LV segments. Image quality was graded as follows: good if 0-1 segments were poorly visualized; moderate if 2-3 segments were poorly visualized; poor if 4-5 segments were poorly visualized; and insufficient if > 5 segments were poorly visualized or if image quality was significantly compromised due to other factors. In DCM group, image quality was graded in the remaining 61 patients as insufficient in 7 (11%), poor in 9 (14%), moderate in 23 (37%), and good in 22 (36%). In NC group, image quality was graded in 59 subjects as insufficient in 7 (11%), poor in 9 (15%), moderate in 19 (32%), and good in 24 (39%).All the subjects were examined in the left lateral position, and ECG were recorded simultaneously. In this section, Artida PST-30SBT(1-5 MHz) phased-array transducer was used. After standard echocardiographic studies, in which end-diastolic diameters, end-systolic and end-diastolic volumes and ejection fractions were assessed using the biplane method according to the modified Simpson's rule, informed consents were obtained from those patients eligible for inclusion.3DT was performed with Artida PST-25SX transducer (1-4 MHz) by one experienced operator. Apical full volume acquisition was obtained in all subjects to visualize the entire LV in a volumetric image within one breath hold. For acquisitions of a full-volume data set, six smaller real-time volumes, acquired from consecutive cardiac cycles, are combined to provide a larger pyramidal volume. Care was taken to optimize the temporal and spatial resolution of images by decreasing depth and sector width as much as possible while retaining the entire LV within the pyramidal volume. In this study, the frame rate was (21 ± 3) volumes/s.Three-dimensional speckle-tracking analysis was performed by one experienced observer on-line. Each 3D data set was displayed in a 5-plane view: (A) an apical 4-chamber view; (B) a second apical view orthogonal to plane A; and (C) 3 short-axis planes: plane C1 in the apical region, plane C2 in the midventricle, and plane C3 at the basal portion of the left ventricle. The user then set three markers on planes A and B; in each plane, one marker was set at the apex and the other two at the edges of the mitral valve ring. The software then detected the LV endocardium, and the user set a default thickness for the myocardium. After the markers had been selected, the system performed the wall motion-tracking analysis through the entire cardiac cycle. For each consecutive time frame, LV volume is calculated by voxel count inside the detected endocardial border. End-diastolic volume (EDV) and end-systolic volume (ESV) were then obtained from the LV volume curve as the respective maximum and minimum values, concurrently providing the calculated LVEF. The LV was divided into 16 segments  on the basis of the American Heart Association standards for myocardial segmentation , and eact test was used for comparison between DCM group with NC group. Multiple comparisons among different planes were performed using analysis of variance (ANOVA) with post hoc SNK. Interobserver variability was assessed by analyzing 10 subjects chosen randomly by 2 independent investigators. For intraobserver variability, 10 subjects were analyzed by one investigator twice within 4 weeks, and the mean of the sixteen segments for RS, CS and LS were calculated, respectively. To assess test-retest reliability, a complete echocardiographic re-study was performed in 20 randomly selected subjects within 1 h after the first study without alteration of haemodynamics or therapy. Each study was subsequently analysed by different observers to best reflect daily clinical practice. The estimation of interobserver, intraobserver and test-retest reproducibility was performed using the intraclass correlation coefficient (ICC) and Bland-Altman plots. Pearson linear correlation method was used to analyze the correlation between 2D-derived and 3D-derived LV measurements. A P value less than 0.05 was considered to be statistically significant.Statistical analysis was carried out using SPSS version 13.0. Quantitative data were expressed as mean ± SD. Independent-samples P > 0.05), while LVDd, LVEDV, LVESV, LVEF, LVEDVI, and LVESVI decreased significantly in DCM group . Whereas the regularity could not be applied to the DCM group, as there were no significant differences between any two planes  in patients with DCM, the left ventricle undergoes complex changes in geometry, by alteration of the left ventricular (LV) chamber and myocardial systolic and/or diastolic function. Determination of myocardial function is very important and necessary in the clinical evaluation of non-ischemic DCM. It not only assists in the diagnosis, but also provides important prognostic and management information. Nowadays, echocardiography is the imaging modality most widely utilized to assess left ventricular (LV) myocardial function, and the most widely used clinical tool to quantify LV systolic function is ejection fraction (EF), but it utilizes a simplistic approach that correlates most closely to the radial performance of the myocardium. Strain and Strain Rate imaging allow for a more precise characterization of the mechanics of myocardial contraction and relaxation (deformation imaging).Strain can be determined by either tissue Doppler or two-dimensional speckle tracking. The prior method is influenced by the angle between the direction of ultrasound beam and myocardial motion . TherefoThe orientation of the fibers in the intact LV wall are complicated, which change from an oblique orientation at the epicardium to a circumferential orientation at the midwall and then to a reverse oblique direction at the endocardium . That isIn the present study, all myocardial deformational parameters, including radial, circumferential and longitudinal strain were significantly lower in patients with DCM than in the control group, which was in agreement with previous reports of depressed contractility in patients with DCM ,29. A laIn our study, we found that normal regional strain curve showed consistent shapes with a single peak, and the peak systolic strain in different planes had certain regularities. CS and LS were largest in the apical region and smallest in the basal region, which was in accordance with previously reported works using 3D-STE and 2D-STE ,32 and mOur results should be considered in the context of several limitations. First, this study covered a small number of patients at a single center, so that further studies of larger patient populations will be needed. Second, time and spatial resolutions of 3D-STE are relatively low. Thus, the low frame rate of 3D-STE could cause miscorrelation between frames and possibly may have affected tracking quality and strain data. This is a usual limitation in ultrasound, and we are waiting for improvements.Third, in our work, data on 3D-STE were obtained using a particular platform and a specific implementation of wall-motion-tracking software. It may not be assumed that identical data would be obtained using a different platform or a different tracking algorithm. In previous studies, the inter-vendor consistency of speckle-derived indices has been investigated ,35, and The newly developed technique of 3D-STE is a reliable tool for evaluation of left ventricular myocardial strain in patients with non-ischemic DCM, and the interobserver and intraobserver agreement and test-retest reliability were acceptable. Furthermore, 3D LV volumes and ejection fractions were simultaneously provided together with 3D strain values, which is a huge advantage in clinical application.The authors declare that they have no competing interests.FXD and MXX have made substantial contributions to study conception and design, acquisition of data, analysis and interpretation of data. XFW, YML and LH have been involved in revising study critically and have given final approval of the version to be published. LJ and QF have been involved in acquisition and analysis of data, and given final approval of the version to be published. All authors read and approved the final manuscript.


Early detection of left ventricle (LV) systolic dysfunction is essential for management of patients with aortic stenosis (AS). Two- dimensional speckle tracking derived global longitudinal peak strain (GLPS) is more sensitive than ejection fraction (EF) but requires good image quality and is not easily accessible. The aim of the study was to compare GLPS with traditional echocardiographic parameter- mitral annular plane systolic excursion (MAPSE) in AS.In consecutive patients with moderate to severe AS and LV ejection fraction ≥ 50% standard echocardiography and two-dimensional speckle tracking echocardiography were performed. Mitral annular plane systolic excursion and global longitudinal peak strain were obtained from apical echocardiographic views.2, p = 0.005).A total of 82 patients were examined, median age was 68 (60–78), 56% of them were men. There was a positive correlation between aortic valve area index (AVAI) and: MAPSE , MAPSE indexed for body surface area- MAPSEI  and GLPS  but not EF . A positive correlation was found between GLPS and MAPSE  and between GLPS and MAPSEI . All above parameters were significantly lower in symptomatic patients compared to asymptomatic subjects  vs. 6.46 ± 0.97 mm/mDespite the development of the modern echocardiographic techniques, mitral annular plane systolic excursion can still be used as a sensitive tool to detect early longitudinal LV systolic dysfunction. Aortic stenosis (AS) is the most common type of valvular heart disease . Early dConsecutive patients with moderate to severe AS and preserved LV systolic function (LVEF ≥ 50%), diagnosed in Cardiac and Vascular Diseases Department, Jagiellonian Unievestity Medical College, Krakow, Poland were enrolled. All patients underwent physical examination, standard blood analysis and transthoracic echocardiography. Detailed medical histories were taken, including the presence of AS symptoms . Exclusion criteria included: unstable coronary artery disease (CAD), LVEF < 50%, regional LV wall motion abnormalities, concomitant moderate or severe disease of another valve, mitral annular calcification, atrial fibrillation and severe renal or hepatic insufficiency.The study was approved by the local ethics committee of the Jagiellonian University and written informed consent was obtained from all the participants.2 or AVA index (AVAI) < 0.6 cm2/m2.Transthoracic echocardiography was performed using Vivid Seven GE Medical Systems equipment  and digitally stored for further analysis on the EchoPAC version 108.1.12 . Measurements were undertaken in the left lateral decubitus position. LV end-systolic volume (LVESV), end-diastolic volume (LVEDV) and ejection fraction were measured by the modified bi-plane Simpson rule, LV mass were calculated using ASE formula . The mea2 test for categorical variables. The Pearson’s or Spearman’s correlation was used to examine linear correlation between the numerical variables. Receiver operating characteristics curve (ROC) analysis with area under the curve (AUC) calculation was used for the determination of cut-off values of MAPSE and GLPS o predict clinical symptoms. The value of p < 0.05 was considered statistically significant.Statistical analysis was performed using the STATISTICA 10.0 software. The Shapiro-Wilk test was used to determine normal distribution. Levene’s test was used to determine the homogeneity of variance. Continuous variables are shown as mean ± standard deviation (SD) or median and interquartile range (IQR). Categorical variables are presented as the number of patients and percentage. Comparisons between the groups were made by t-test for normally distributed continuous variables, Mann- Whitney U test for non-normally distributed continuous variables and χA total of 82 patients were studied. Of these, 55 patients (67%) had severe AS. The median age was 68 (60–78) years, 46 (56%) of them were men. Patients were divided into the two subgroups according to their symptomatic status: 53 patients (65%) were symptomatic and 29 (35%) were asymptomatic. Basic demographic and clinical data of the patients are summarized in Table 2/m2, with the mean ejection fraction of 63 ± 7%. By definition, patients with severe AS had higher transaortic gradients and lower AVA and AVAI. They also have significantly higher left ventricle end-systolic volume index and lower GLPS, MAPSE and MAPSE index (MAPSEI) compared to moderate AS patients. The echocardiographic characteristics of the study population is presented in Table In the whole group median AVAI was of 0.45 0.36-0.62) cm cm2/m2, There was a positive correlation between AVAI and: MAPSE , MAPSEI  and GLPS , but not with EF , as presented in Figure EF correlated weakly with GLPS  and MAPSEI  but not with MAPSE .A good positive correlation was found between GLPS and MAPSE  and between GLPS and MAPSEI , what is shown in Figure Patients with symptoms were significantly older than those asymptomatic while other demographic and clinical data such as prevalence of hypertension, diabetes or coronary artery disease were comparable between these subgroups Table .However, symptomatic patients had significantly higher transvalvular peak and mean pressure gradients and a lower AVAI compared to asymptomatic subjects. Furthermore, all parameters quantifying longitudinal LV function  were significantly lower in symptomatic subgroup, as presented in Table Both GLPS and MAPSE had similar area under the curve (AUC) for symptoms prediction, p = 0.933, as shown in Figure In the present study, we show that 2D speckle tracking derived global longitudinal peak strain, mitral annular peak systolic excursion, as well as mitral annular peak systolic excursion index correlate inversely with the severity of AS. Moreover, there was a good correlation between GLPS and MAPSE and MAPSEI. All of these parameters quantify long-axis LV systolic function.Although more than 50% of the stroke volume is generated by the longitudinal LV contractility ,20, ejecSpeckle tracking echocardiography has been described as a method assessing LV multidirectional function. This technique enables to quantify global and regional LV contractility -13. ManyCurrently, in the era of the development of more advanced techniques, the measurement of the atrioventricular plane displacement may seem to be unnecessary. However, it may be of great value in many cases. MAPSE does not require good acoustic window, thus can by applied when visualization of the endocardial borders is not obtainable. Moreover, this old technique can be performed at the bedside. In the study of Bergenzaun et al. , performWhile there are no standards concerning the point where MAPSE should be measured, we decided to use the average value from septum and lateral wall.The data concerning the relationship between 2D-STE derived global longitudinal peak strain and mitral annular plane excursion in aortic stenosis are limited. GLPS is a parameter calculated from all 17 LV segments while MAPSE in the present study was assessed in the LV lateral wall and interventricular septum only. Thus, the measurement of MAPSE is more simple and does not require good image quality of all LV segments- only the mitral annulus, being the highly accessible and sensitive method of early LV function impairment in aortic stenosis. Of note, in the current study, all LV function parameters  were decreased in symptomatic patients, while there was no difference in ejection fraction between these subgroups, what may have the prognostic clinical value.Furthermore, both GLPS and MAPSE were characterized by having the AUC for symptoms prediction exceeding 0.7, and that could differentiate symptomatic from asymptomatic patients. Similar observation with regard to GLPS were obtain by Laffite et al.  with theThe main limitation of this study is heterogeneity of the study group. The concomitant diseases may impinge on the left ventricle longitudinal contractility. Nevertheless, we have decided to include patients with hypertension, diabetes and coronary artery disease because those diseases are common in the population of patients with aortic stenosis.MAPSE may usually be normalized to the heart size. However, in this study, we indexed MAPSE to the body surface area, as we did with the other values: aortic valve area, left ventricle mass and volumes.The present study suggest that, in spite of the development of the modern echocardiographic technologies, mitral annular plain systolic excursion can still be used to asses LV systolic longitudinal function. The advantage of this older technique may particularly be seen in suboptimal acoustic windows or when the dedicated software for speckle tracking echocardiography is not available.The authors declare that they have no competing interests.JL designed the study, collected the data, interpreted the data and drafted the article. MO participated in the design of the study and helped to draft the manuscript. SD collected the data and interpreted the data. WP interpreted the data and helped to draft the manuscript. MKW and IK collected the data. PP interpreted the data. All authors read and approved the final manuscript.


Successful infant heart transplantation has now been performed for over 25 years. Assessment of long term outcomes is now possible. We report clinical outcomes for322 patients who received their heart transplant during infancy. Actuarial graft survival for newborn recipients is 59% at 25 years. Survival has improved in the most recent era. Cardiac allograft vasculopathy is the most important late cause of death with an actuarial incidence at 25 years of 35%. Post-transplant lymphoma is estimated to occur in 20% of infant recipients by25 years. Chronic kidney disease grade 3 or worse is present in 31% of survivors. The epidemiology of infant heart transplantation has changed through the years as the results for staged repair improved and donor resources remained stagnant. Most centers now employ staged repair for hypoplastic left heart syndrome and similar extreme forms of congenital heart disease. Techniques for staged repair, including the hybrid procedure, are described. The lack of donors is described with particular note regarding decreased donors due to newer programs for appropriate infant sleep positioning and infant car seats. ABO incompatible donors are a newer resource for maximizing donor resources, as is donation after circulatory determination of death and techniques to properly utilize more donors by expanding the criteria for what is an acceptable donor. An immunological advantage for the youngest recipients has long been postulated, and evaluation of this phenomenon may provide clues to the development of accommodation and/or tolerance. Infant heart transplantation was first attempted by Adrian Kantrowitz 3 days after Christiaan Barnard’s famous first transplant performed in 1967. Magdi Yacoub in London performed a heart transplant on a 10-day-old baby in 1984. The infant survived 18 days. In the fall of the same year, Leonard Bailey and the team at Loma Linda University performed a xenotransplant operation, inserting the heart of a baboon into a 12-day-old baby who survived 20 days. The first successful infant recipient was transplanted by Denton Cooley in 1984 and this child survived 13 years. The first successful newborn heart recipient was transplanted at Loma Linda in 1985 at the age of 4 days. He is still alive and well, with his first graft, 25 years later [There have been 8575 pediatric heart transplant procedures reported to the International Society for Heart and Lung Transplantation Registry through 2009 .In the last quarter century, much has been learned about infant heart transplantation. But, much remains to be discovered. This report will describe the clinical outcome of infant heart transplant recipients, utilizing the Loma Linda experience, concentrating on survival, rejection, cardiac allograft vasculopathy, post-transplant lymphoproliferative disease and long-term renal function. In addition, we will describe issues that are especially pertinent to infant heart transplantation; donor availability, ABO incompatible transplantation, surgical management of infants with hypoplastic left heart syndrome (HLHS) and similar extreme forms of congenital heart disease, and transplantation and the hybrid procedure for palliation of HLHS.1 illustrates the number of transplant procedures in newborns (0-30 days) and infants (1-12 months) by year. One can see that the proportion of newborns transplanted has declined, illustrating the change in donor availability over time.There have been 322 infant heart transplant procedures performed at Loma Linda University Children’s Hospital from November 1985 through November 2010. Of these, 103 or 32 % were performed during the first month of life, with the youngest transplanted at 1.5 hours of life . Early i2. Newborn recipients have better survival than those transplanted later in infancy. The reason for this is probably multi-factorial and likely includes an immunological advantage to early transplant (discussed below) and avoidance of complications that arise with prolonged waiting time. The graft half-life for newborn recipients is still undefined, with an actuarial graft survival at 25 years of 59%, likely the longest graft half-life for any solid organ transplant population.The actuarial survival for these patients is illustrated in Fig. 3.There has been an era effect similar to effects reported in the ISHLT registry report. This is illustrated in Fig. The causes of death are similar to what one might expect, with acute and chronic rejection  being the most significant . Acute rOur immunosuppression regimen has evolved over the years, but it has consistently had the goal of steroid avoidance. Less than 5% of our infant recipients require maintenance steroids to prevent rejection. Similar shorter term outcomes have recently been demonstrated by the Boston Children's group . Our cur4. Between 10 and 20 years after infant heart transplantation approximately 30% of patients will experience a rejection episode. There is a particular hazard of rejection during adolescence when issues of non-adherence become more important.Acute rejection late after infant heart transplantation occurs, as illustrated by Fig. 5.Consistent with other reports,  cardiac 6). Interestingly, the time to infection parallels the risk of PTLD with essentially all infant recipients predicted to have been infected by Ebstein Barr Virus (EBV) by 19 years after transplant. Post-transplant lymphoproliferative disease (PTLD) is another important cause of late morbidity and mortality. In a multi-center report , the pro7. The average i-GFR in these patients is 73 mL/min/1.73m2. However, there are a significant number of patients with significant renal insufficiency and 7 infants have received renal replacement therapy late after heart transplantation. The number of patients in each category of chronic kidney disease (as defined solely by their GFR) is illustrated in Table 1.Long-term renal function is a particular concern in a population that is hoped to survive for decades after transplant. It is a particular concern in the infant population since they are transplanted before kidney maturity has occurred. Of those infants who have survived at least 10 years, 47% are receiving anti-hypertension therapy. We have also undertaken a program of thorough evaluation of renal function, performing an isotopic glomerular filtration rate (i-GFR) on an annual basis on all patients followed at our institution. The most recent i-GFR for 93 infant recipients who have survived at least 10 years is noted in Fig. There is now a 25 year history of successful infant heart transplantation. Much has been learned, but much remains to be understood. The following will describe those issues most applicable to infant heart transplantation:Which congenital heart lesions should be managed with heart transplantation as primary therapy, if any?What is the optimal approach to hypoplastic left heart syndrome and equivalent malformations?How might the supply of donors be improved?Is there an immunologic advantage for the younger recipient?Hypoplastic left heart syndrome (HLHS) was once considered beyond surgical relief. Infants born with it, died because of it. During the past quarter-century, however, the story has dramatically improved. Norwood’s staged-reconstruction and infant heart transplantation grew out of the early 1980’s to create a positive change in survival for infants with this and similar extreme forms of congenital heart disease . NeitherA). Alternatively, a polytetrafluoroethylene (PTFE) tube is used to connect the base of the ventricle to the branch pulmonary arteries, a modification introduced by Sano and colleagues  [Both understanding and application of Norwood’s staged-reconstruction has evolved brilliantly during the past two decades. The approach now includes three separate stages. The first, and most challenging stage is accomplished in the neonate. It involves aortic arch reconstruction  and uses the native pulmonary valve for systemic ventricular outflow. The pulmonary circulation is separated from the heart and is driven by means of a modified Blalock-Taussig shunt  . The atrAs many as 9 out of 10 neonates now survive Norwood’s first stage of reconstruction. Survival following stage-one reconstruction appears to be independent of the source of pulmonary blood flow; i.e., Blalock-Taussig shunt vs. Sano conduit, but many believe that perioperative management is less stressful for infants who have Sano’s modification. While there remains some interstage attrition, the vast majority of these babies reach consideration for a second stage procedure.9). This is the procedure used at Loma Linda. Any additional aortic arch reconstruction or atrioseptectomy is accomplished at the second stage.The second stage of reconstruction is applied between four and eight months of age and requires adequate preoperative physiology in the form of low pulmonary pressure and resistence, good ventricular and atrioventricular valve function. Stage-two varies depending upon the projected form the final Fontan stage will take. If an intra-atrial lateral tunnel or if a catheter-based completion of the Fontan circuit is anticipated, then stage-two reconstruction usually consists of a so-called “hemi-Fontan” procedure. This involves interruption or takedown of the first-stage source of pulmonary blood flow and creation of bidirectional superior vena caval-to-pulmonary artery flow that incorporates the superior pole of the right atrium. The atrial cavity is separated from the pulmonary circulation by means of a thin baffle of tissue or PTFE. This sets the stage for intra-atrial lateral tunnel Fontan completion. If catheter-based completion is anticipated, a short circular tube of PTFE is sutured around the inferior vena caval entrance to the atrium. This becomes an attachment site for a covered stent extending from the inferior vena cava to the pulmonary artery. Alternatively, the second stage procedure is nothing more than takedown of the previous source of pulmonary blood flow and creation of a bidirectional cavopulmonary (Glenn) anastomosis  [Timing of the final or third stage varies depending upon the anticipated type of Fontan completion. Many centers, including Loma Linda, complete the final stage of reconstruction between 18 and 24 months of age. A pedicled tube of autologous pericardium is utilized for extracardiac Fontan completion at Loma Linda  . 11). Those centers using an extra-cardiac prosthetic conduit may choose to delay the final stage to age three or four in an effort to accommodate a larger inferior vena cava-to-pulmonary artery conduit . A more recent innovation in the management of HLHS is the so-called hybrid approach. It consists of bilateral pulmonary artery banding, accomplished surgically via sternotomy, with either simultaneous or delayed catheter-based stenting of the patent ductus arteriosus. This is coupled with balloon atrioseptostomy   and mandThe incidence of SIDS has been dramatically reduced in the last 15 years . Still, Cardiac transplantation in infancy using ABO incompatible donors in the appropriate setting  has now Donation after Circulatory Determination of Death (DCDD) has potential to impact the donor supply . In a reA more fruitful source of potential donors might be those potential donors who are not used for transplantation. Between 2000 and 2008, nearly 35% of pediatric donors in the UNOS database were not used for transplantation. It is possible that the smaller recipient pool could make it likely that there wouldn’t be a suitable recipient for every given donor. However, there are many donors turned down for reasons of presumed unsuitability of the graft. A series of 29 pediatric heart transplant procedures, utilizing grafts that had been turned down because of presumed graft unsuitability, was shown – even in the face of prolonged ischemic time – to not affect transplant survival .Increasing the donor pool is in many ways more important than what occurs after transplant, for the mortality prior to transplantation in infants is higher than one year mortality after transplantation. It appears that routine listing for ABO-incompatible donation in the appropriate setting and a willingness to consider donors that appear to be unsuitable should be routine practice in pediatric heart transplant centers.One of the earliest experiments in transplantation, conducted by Billingham and Medawar . demonst2, 4 and 5. Newborn “tolerance” is probably multi-factorial, and has been the subject of many theories. Is there negative selection, as occurs in natural self-tolerance? [The immune reaction to allotransplantation has been described as universal, rapid and severely destructive . And, inlerance?  Or, is tlerance? . What welerance? . This ocThe infant who has undergone heart transplantation, with concomitant removal of the thymus, may provide important clues to the interplay between the thymus and immunosuppression in the immature human. The T-cell receptor diversity in the blood of infants who undergo heart transplantation during infancy has been shown to be markedly diminished. The normal person has approximately one billion different T cells. Some infant heart transplant recipients have as few as 1000. In addition, thymic function, as deduced from levels of human herpesvirus 7 was notably impaired .There has been an increased risk of infections in infant heart transplant recipients, even late after transplantation. Interestingly, an increased risk of autoimmune disease was also noted .The infant heart transplant recipient is likely to provide important clues to the development of accommodation and/or tolerance, and they should be studied with increased vigor.Heart transplantation during infancy has now been successfully performed for 25 years. Much has been learned, but much remains to be learned. Since a lifespan after infant heart transplantation is potentially much longer than for an adult recipient, it is imperative to more aggressively pursue methods to prevent and treat those long-term morbidities most likely to impact longevity – cardiac allograft vasculopathy, post-transplant lymphoproliferative disease, and long-term kidney function. Not noted in this review, but addressed elsewhere in this issue of the journal, is the challenge of non-adherence, particularly during adolescence.Surgical techniques have been refined, and the debate about staged repair versus transplantation for HLHS and equivalent lesions has, because of improved results with staged repair and continued lack of sufficient numbers of suitable donors, been settled in favor of staged repair. Transplantation as primary therapy is now reserved for patients with severe valve regurgitation and/or significantly impaired ventricular function. Many of these patients, however, will come to transplantation after any of the repair stages. And, these patients, because of chronic illness and increased anti-donor antibodies, are more challenging to transplant.The lack of suitable donors continues to limit the full expression of what could be superior therapy for many infants. Salutary public health initiatives, such as the change in infant sleep positions and mandatory infant car seats, have decreased the number of suitable donors. But, there are still many donors who are not used due to concerns, which may not be valid, regarding their suitability for transplantation.Lastly, there is an apparent survival advantage for the youngest recipients. The graft half-life for newborn heart transplant recipients is still undetermined even 25 years later. Part of this advantage appears to be immunological. Transplantation for infants in the setting of ABO-incompatibility is possible because of their lack of pre-existing isohemagglutins, and leads to tolerance for the “incompatible” antigen. A preliminary picture is developing of the changes that occur in infants who are transplanted early in life, and who have removal of the thymus and then introduction of T-cell depleting agents and immunosuppression. But, there is still a conspicuous lack of understanding of just what might be other immunological factors involved in the so-called “neonatal window of opportunity”.Apart from the more widespread introduction of safer mechanical assist devices in this population, it is unlikely that major changes will occur in surgical management. The current frontier for infant heart transplantation will be in the management of the sensitized recipient, improved prevention and management of long-term complications, and a better understanding of the immunologic milieu.


Mural endocardial lesions can be seen as MacCallum plaques in rheumatic heart disease. These plaques appear as map-like areas of thickened, roughened, and wrinkled part of the endocardium in the left atrium. Perhaps they are caused by regurgitant jets of blood flow, due to incompetence of the mitral valve. Although MacCallum plaques are one of the characteristic features in rheumatic heart disease, they are very uncommon in recent times. We hereby report a case of an adolescent female with RHD, who was working as a housemaid in a doctor’s house for a few months, and suddenly developed respiratory tract infection and cardiac failure. She died on the fourth day of admission. A medicolegal autopsy was conducted, as her relatives accused her master of sexual assault. On autopsy it was seen that the mitral valves were narrowed, showing multiple vegetations. MacCallum plaque was seen in the dilated left atrium. Hence, it is presented here for educative purposes. In India and other developing countries, rheumatic fever (RF) and rheumatic heart disease (RHD) continue to be major public health problems and contribute to significant cardiac morbidity and mortality. RF is an1About 60% of acute RF patients with cardiac failure, develop valvular diseases 10 years later. They havAn adolescent female, about 18 years of age, with RHD, was working as a housemaid in a doctor’s house for a few months. She or her parents did not reveal her disease status to her employer in spite of knowing it before hand. She was on irregular treatment with no improvement. One day she suddenly developed respiratory tract infection and was hospitalized. She was diagnosed as a case of RHD complicated with heart failure. She died on the fourth day of admission. A medicolegal autopsy was conducted as her relatives accused her master of sexual assault and demanded heavy compensation.On opening the pleural and pericardial cavities, about one liter of pus was drained. The heart weighed 282 g. The left atrium showed dilatation, with a map-like thickened, roughened, and wrinkled area in the posteromedial surface , which wHistopathological examination of multiple sections from the thickened and fibrosed area in the left atrium revealed diffuse subendocardial fibrosis ; the areIn India and other developing countries, RF is common and is responsible for many cases of damaged heart valves. In Western countries, it has become fairly rare since the 1960s, probably due to the widespread use of antibiotics to treat streptococcal infections. Acute RF2Rheumatic fever is a systemic, poststreptococcal, nonsuppurative inflammatory disease, principally affecting the heart, joints, central nervous system (CNS), skin, and subcutaneous tissues. William 1212Rheumatic heart disease is the major cause of morbidity from rheumatic fever. Acute RHD often produces pancarditis, characterized by endocarditis, myocarditis, and pericarditis. The infl22Subendocardial lesions may induce irregular thickening called MacCallum plaques, usually in the posterior wall of the left atrium just above the posterior leaflet of the mitral valve. Perhaps MacCallum plaques are caused by regurgitant jets of blood flow due to incompetence of the mitral valve.575The chronic stage of RF is characterized by pancarditis, causing major cardiac sequelae, referred to as RHD, with permanent deformity of one or more valves. A chronic healed mitral valve shows ‘fish mouth’ or ‘buttonhole’ stenosis.6 Chronic12A characteristic feature of the microscopic examination of acute RF is the presence of Aschoff bodies consisting of swollen eosinophilic collagen surrounded by lymphocytes, occasional plasma cells, and plump macrophages, called Anitschkow cells. These Anitschkow cells have abundant cytoplasm and central round-to-ovoid nuclei in which the chromatin is disposed in a central, slender, wavy ribbon (hence the designation ‘caterpillar cells’). Some of these become multinucleated to become Aschoff giant cells. These bodies can be found in any of the three layers of the heart. A microscopic examination of chronic RHD shows diffuse fibrosis and often neovascularization that obliterates the originally layered, avascular leaflet architecture. Aschoff bodies are replaced by a fibrous scar; therefore, diagnostic forms of these lesions are rarely seen in surgical specimens or autopsy tissues of patients with chronic RHD.5Once the heart is involved it is often associated with reactivation and recurrence of the disease. Myocarditis in particular is the most life-threatening complication, due to involvement of the conduction system of the heart and results in serious arrhythmias. Major ca5Streptococcus pyogenes.Prevention of RHD is achieved by eradicating the acute infection and prophylaxis with antibiotics to decrease mortality and morbidity. Primary care physicians and nurses also play a role in the prevention, primarily in screening school-going children for sore throats that may be caused by Group A β-Hemolytic One of the characteristic features of rehumatic heart disease on histology is the finding of MacCallum’s plaques. To demonstrate MacCallum’s plaques, multiple sections from thickened and fibrosed areas, especially from the left atrium should be obtained on histopathological examination.


Rupture of the ventricular myocardium is an often lethal complication after myocardial infarction. Due to the dramatic hemodynamics and the short time frame between ventricular rupture and surgical closure of the defect, additional therapeutic strategies are needed. Here we report the successful therapy of ventricular rupture by percutaneous intrapericardial instillation of fibrin glue in a 72-year-old male patient with postinfarct angina secondary to anterior myocardial infarction. Rupture of the ventricular myocardium after myocardial infarction is a dramatic and often lethal complication. Due to the dramatic hemodynamic dysfunction, immediate therapies are imperative. As surgical repair of the defect is often not available, percutaneous intrapericardial instillation of fibrin glue can be an alternative.ultima ratio, we instillated a total of 30 mL of a two-component fibrin glue normally used for bleeding ulcers in gastroenterology. This resulted in a sustained hemodynamic stabilization. The patient could be weaned off the balloon pump and catecholamines in the following three days. Echocardiography showed a stable minor pericardial effusion of 100 mL without any signs of hemodynamic relevance (A 72-year-old male patient with postinfarct angina secondary to anterior myocardial infarction was transferred to our center from a community hospital after administration of systemic thrombolytic therapy using streptokinase. Coronary angiography showed single vessel disease with high grade stenosis of the LAD. Stent implantation was successfully performed with uncomplicated postinterventional course. On day three, the patient developed another episode of angina. Recatheterization excluded acute restenosis or stent thrombosis. On the same day, the patient developed rapid onset cardiogenic shock with need for resuscitation, intubation, high dose catecholamine treatment, and an intra-aortic balloon pump. Echocardiography showed an acute pericardial tamponade suggesting a ventricular rupture . Pericarelevance . Unfortuelevance . No releRupture of the ventricular wall is an often lethal complication of acute myocardial infarction. Besides myocardial infarction ventricular rupture has also been reported after cardiac trauma, valve replacement, and cardiac tumors. In the setting of myocardial infarction ventricular rupture occurs in 2%–6% of all patients and is third to cardiogenic shock and arrhythmias as the leading cause of death after myocardial infarction . The majWhen immediate heart surgery is not available or applicable as in our case, intrapericardial injection of fibrin glue as reported here facilitates an alternative treatment in this desperate situation. Autopsy revealed focal peri- and epicardial adhesion of the defect by fibrin glue, proving its effectiveness. Murata et al. reported similar results on autopsy after intrapericardial fibrin injection . IntrapeThis and the few other case reports on the medical treatment of left ventricular wall rupture are by far not sufficient to provide a general recommendation; however, due to its dramatic presentation and often lethal outcome, intrapericardial fibrin injection should be considered in patients with an oozing rupture of the ventricular wall as a last resort.


Three dimensional echo is a relatively new technique which may offer a rapid alternative for the examination of the right heart. However its role in patients with non-standard ventricular size or anatomy is unclear. This study compared volumetric measurements of the right ventricle in 25 patients with adult congenital heart disease using both cardiovascular magnetic resonance (CMR) and three dimensional echocardiography.Patients were grouped by diagnosis into those expected to have normal or near-normal RV size (patients with repaired coarctation of the aorta) and patients expected to have moderate or worse RV enlargement . Right ventricular end diastolic volume, end systolic volume and ejection fraction were compared using both methods with CMR regarded as the reference standardBland-Altman analysis of the 25 patients demonstrated that for both RV EDV and RV ESV, there was a significant and systematic under-estimation of volume by 3D echo compared to CMR. This bias led to a mean underestimation of RV EDV by -34% (95%CI: -91% to + 23%). The degree of underestimation was more marked for RV ESV with a bias of -42% (95%CI: -117% to + 32%). There was also a tendency to overestimate RV EF by 3D echo with a bias of approximately 13% (95% CI -52% to +27%).Statistically significant and clinically meaningful differences in volumetric measurements were observed between the two techniques. Three dimensional echocardiography does not appear ready for routine clinical use in RV assessment in congenital heart disease patients with more than mild RV dilatation at the current time. Monitoring of serial change in right ventricular (RV) size and function is of fundamental importance for physicians caring for patients with paediatric and adult congenital heart disease (ACHD) ,2. Two dRecently, three dimensional echocardiographic (3D echo) techniques have been introduced which are capable of acquiring a real time volumetric data set using ordinary commercially available echocardiography systems. Such data can be rapidly collected at the bedside and can be processed off-line in a similar manner to CMR data. If accurate and reproducible, this modality could simplify serial data collection in patients known to be at risk of the deleterious effects of right heart dilation and dysfunction. The purpose of this study was to report our initial experience of 3D trans-thoracic echo as a possible alternative to CMR in an ACHD population with a range of right ventricular volumes and functional abnormalities.Patients were recruited in a prospective, consecutive manner from the Adult Congenital Heart Disease out-patient program at our institution. Patients were eligible if they had undergone a CMR examination in the preceding 12 months, or if the responsible physician indicated that CMR exam would be performed in the subsequent 6 months. Recruitment was restricted to 3 groups; those with previously repaired Tetralogy of Fallot (ToF) in infancy or childhood ; those with a right ventricle in the systemic position  and those with repaired coarctation (CoA) of the aorta. Patients within the first 2 groups were expected to have a range of RV dilatation and dysfunction, and for the purpose of analysis were treated as a single group. The coarctation group were included as an internal control arm with the expectation that right ventricular size and function would be normal or near-normal. The study was approved by the Institutional Review Board and all subjects gave written informed consent.All patients underwent a full 2D trans-thoracic echocardiogram with particular focus on the right ventricle according to the recommendations of the American Society of Echocardiography . All imaAll RV contours were performed on the short axis cine stack from the pulmonary valve to the RV apex, with trabeculation assigned to the blood pool [CMR examinations were performed on a Philips 1.5 T Intera magnet . Steady state free precession (SSFP) images were acquired in the short axis plane from the atrioventricular groove to the cardiac apex. Cine acquisitions were performed with vectorcardiographic ECG gating over 6-10 heartbeats at held end-inspiration. Technical parameters were: slice thickness 8 mm no gap, 25 cardiac phases, TR 3.2 ms, TE 1.6 ms, FoV 320 × 320 cm, reconstruction matrix 256 × 256 cm. CMR studies were analysed offline using QMass V6.1 software . ood pool .Data are presented as mean (± SD). Descriptive statistics were used for normally distributed data. Non parametric statistics were employed to compare differences in volumes and function where appropriate. Fishers exact test was used for the comparison of proportions. Intra- and inter- observer analysis were tested for both techniques after an interval of 8 weeks by the original readers and a further reader analyzing a random selection of 50% of the cases from each imaging modality. Intra-class correlation coefficients were calculated to rate both inter and intra-observer variability in measurements of RV size and function. The method of Bland and Altman was used for assessment of systematic bias between methods of measurement [Twenty nine patients were recruited to the study over a 12 month period. Three patients failed to complete the study due to CMR-related claustrophobia and in 1 patient 3D echo was unsuccessful due to a combination of difficult echo window and extreme cardiac rotation. The study group was therefore comprised of 25 patients who underwent both 3D echo and CMR within a mean of 12 weeks of each other. Seven patients had a diagnosis of CoA, 14, had ToF and 4 had a diagnosis of complete transposition of the great arteries (TGA) palliated with either a Mustard or Senning procedure. The mean age was not significantly different between the 2 groups (CoA 26 yrs vs ToF/TGA 27 yrs p = ns). Detailed patient characteristics are given in Table Using CMR as the reference standard, there was a clear difference in RV size between the CoA group and the mixed lesion group (ToF and TGA). As expected, patients with a diagnosis of ToF or palliated TGA had significantly larger right ventricular end diastolic and end systolic volumes (EDV and ESV) than the patients with repaired CoA; the RV ejection fraction was also significantly lower in the former group Figure .Compared to CMR, 3D echo significantly underestimated volumes in the 25 patients as a whole, although the difference in measured RV ejection fraction (EF) was not significant . One currently available retrospective study suggests a threshold of 180 ml/m2 at which pulmonary valve replacement (PVR) should be considered [Although there are right ventricular data from 3D echo in the pediatric age range, there are only isolated studies in the literature which have attempted to validate 3D echo in adult populations with congenital heart disease ,20. Our nsidered . In realnsidered . NonetheThe inclusion of several patients with transposition of the great arteries and Mustard/Senning repair was merited as these patients have the right ventricle located in the subaortic position. This inevitably leads to secondary hypertrophy and wall thickening, as well as atrio-ventricular valve regurgitation and secondary systemic ventricular enlargement. Serial assessment of the systemic ventricle in these patients is imperative as progressive decline is often an indication for more aggressive therapies including heart transplantation.CMR has been shown to have excellent reproducibility for measurement of both LV and RV size and function , and thiuncorrected for BSA, with a maximum EDV of just 191 ml. This compares with an uncorrected mean (SD) and maximum in our series of 236 (107) ml, and 509 ml respectively. Despite the relatively small RV cavity sizes included, Nesser et al observed: "...on the Bland-Altman scattergram....a tendency for TEE-3D and TTE-3D to underestimate large RV volumes compared with MRI..." - as such their data are entirely concordant with our findings in much larger RVs.Earlier work comparing RV volume measurement by both transthoracic and transesophageal 3D techniques have demonstrated excellent correlations between the 3D echo measurements of RV volume and function compared to both CMR and radionuclide ventriculography . HoweverRecently, Grewal et al examined 25 patients with tetralogy of Fallot using both CMR and 3D echo . AlthougFurther comparable work was published recently by Arnould et al in an adult population suffering from assorted cardiomyopathies . The meaOur results with 3D echo are similarly disappointing with respect to patients with right ventricular enlargement due to congenital heart disease. As we hypothesized, measurements made by CMR and 3D echo were comparable in the coarctation patient group who had normal RV size. However the patient group in whom 3D echo potentially has the most to offer, those with an enlarged RV (e.g. the ToF and TGA groups), demonstrated relatively poor comparison to CMR for volumetric indices. Furthermore 3D echo would have been falsely reassuring with respect to RV ejection fraction in a number of patients in this study.but that this difference may be substantially reduced if CMR-contouring is performed in such a manner as to exclude the trabeculation from the blood pool  [The reasons for the limited accuracy and reproducibility of 3D echo are likely to be multi-factorial: the spatial resolution of 3D echo in full volume mode is substantially lower than that of the native 2D application; limited lateral spatial resolution results in poorly-defined 'fuzzy' endocardial borders in diastole, and creates genuine difficulty in separating endocardium from trabeculation at end-systole. This specific point was touched on in detail in a thoughtful editorial by Mor Avi et al who point out that a similar difference in recorded volume between the 2 techniques is also seen for the left ventricle ractice) . In otheractice) . As Mor ractice) .Secondly, the right ventricle may be difficult even in a normal individual to fully encompass within a pyramidal volume as is required during 3D image acquisition. In many cases the available sector width is simply inadequate for the size of the ventricle, leading to poor or incomplete endocardial definition in the reconstructed views, with adverse effects on the accuracy of contour definition. Future technical developments will no doubt address the difficulties imposed by sector angle limitations. Thirdly, a proportion of patients may have difficult acoustic windows regardless of RV size. Not infrequently this is related to musculoskeletal abnormalities, such as pectus excavatum, which are often seen in patients with congenital heart disease.a 48% exclusion rate from data analysis in 54 consecutive patients scanned, because of inadequate image quality [Finally, a degree of selection bias undoubtedly plays a role in published data. We deliberately included all but one patient in our analysis; this patient was excluded as the 3D echo image quality was so poor that no attempt at contouring could be made. However one recent publication comparing manual versus automated border detection of 3D echo (versus CMR) in a similar population to ours documented  quality . The autWe acknowledge several limitations to our study. Firstly our sample size was relatively small (though not dissimilar to the published literature in this area) and in particular lacked power to clearly define the progressive limitations of 3D echo in reference to graded increases in RV end-diastolic volume. Secondly, although our patient recruitment was prospective and consecutive the 3D echo was not performed on the same day as the CMR study; however the mean time difference was only 12 weeks between studies in which time one would not expect any significant systematic change in RV cavity size in a stable outpatient population. Thirdly, since 3D echo currently acquires a 'pyramid' of data over multiple sequential heartbeats we did not attempt to recruit any patient who was not in sinus rhythm. This is also a relative limitation of CMR which generally requires a stable R-R interval for routine segmented cine imaging. Fourthly we acquired CMR images in end-inspiration rather than end expiration as is done more routinely. This is because 3D echo windows were generally superior at end-inspiration and we wished to match the two techniques as far as possible. Limited volunteer data suggests this entails a risk of 'over-sampling the RV' since the end inspiratory position of the diaphragm may vary by as much as 25% . HoweverThis study provides further data describing a clinically important underestimation of RV volume by 3D echo, particularly in a patient subgroup with moderate or severe enlargement. We observed a systematic underestimation of both RV EDV and ESV when compared to CMR to an extent which has clinical relevance. The degree of underestimation may provide false reassurance to both patient and physician, and could have an adverse impact on appropriate clinical decision making.3D echo is a new and rapidly evolving modality which may in the near future be able to offer the twin benefits of portability and comparable accuracy to CMR. Many factors contributing to the relative inaccuracy of 3D echo are technical issues that will be addressed by further research and product development. However current data suggest caution is warranted when using 3D echo as the principal imaging modality in patients with any greater than mild RV dilatation. Physicians caring for patients in whom management decisions are based upon possession of accurate volumetric data need to be aware of the current limitations in 3D echocardiography. Our data, and others, support the contention that CMR - for the time being at least - remains the standard of reference in this population.The authors declare that they have no competing interests.AMC, JT and JDT were responsible for study design. AMC, JDT and GB recruited patients for the study. GW and JF performed the 3D echo on all the patients included in the study. AMC and NM performed the CMR analysis. AMC and GB performed the 3D echo analysis. AMC and RM were responsible for the statistical analysis. All authors read and approved the final manuscript.Movie 1. A typical example of the 4D model of the right ventricle derived from a trans thoracic 3D echocardiography study.Click here for file


Myostatin is a negative regulator of skeletal muscle mass whose activity is upregulated in adult heart failure (HF); however, its role in congenital heart disease (CHD) is unknown.We studied myostatin and IGF-1 expression via Western blot in cardiac tissue at varying degrees of myocardial dysfunction and after biventricular support in CHD by collecting myocardial biopsies from four patient cohorts: A) adult subjects with no known cardiopulmonary disease , , (n = 5); B) pediatric subjects undergoing congenital cardiac surgery with normal RV size and function , (n = 3); C) pediatric subjects with worsening but hemodynamically stable LV failure [LV and right ventricle ] with biopsy collected at the time of orthotopic heart transplant (OHT), (n = 7); and D) pediatric subjects with decompensated bi-ventricular failure on BiVAD support with biopsy collected at OHT , (n = 3).The duration of HF was longest in OHT patients compared to BIVAD. The duration of BiVAD support was 4.3±1.9 days. Myostatin expression was significantly increased in LV-OHT compared to RV-OHT and RVOT, and was increased more than double in decompensated biventricular HF (BiVAD) compared to both OHT and RVOT. An increased myostatin/IGF-1 ratio was associated with ventricular dysfunction.Myostatin expression in increased in CHD, and the myostatin/IGF-1 ratio increases as ventricular function deteriorates. Future investigation is necessary to determine if restoration of the physiologic myostatin/IGF-1 ratio has therapeutic potential in HF. Therefore, in this study, our goal was to quantify myostatin expression in CHD in patients with both compensated LV failure and with decompensated biventricular failure on BiVAD support. In addition, we also sought to quantify IGF-1 expression, as the relationship between myostatin and IGF-1 in the heart is poorly understood This study met all institutional guidelines and New York State organ donation guidelines regarding use of clinical data, ethical treatment of patients adhering to Declaration of Helsinki principles, and procurement of tissue for research. This study was approved by the Institutional Review Board of Columbia University Medical Center , the New York State Organ Donor Network, and met all institutional guidelines regarding handling of tissue specimens, HIPAA security of clinical information. Tissue from all subjects was collected at Columbia University Medical Center, while tissue from rejected organ donors was collected at local harvest sites, in accordance to New York Organ Donor Network guidelines.Consent for this study for pediatric study subjects (IRB-AAAF0646) was waived by the Columbia University Medical Center Institutional Review Board for the following reasons: 1) all tissue collected was tissue that would otherwise have been discarded, 2) the difficulty of pre-operatively predicting which surgery would yield appropriate type and amount of specimen tissue was too high to require consent for all congenital patients undergoing surgery (our yield for tissue was ∼10/400 surgeries), and 3) the study posed no risk to subjects , and 4) all tissue and clinical data was de-identified. For adult donor hearts , consent for research was documented by the New York State Organ Donor Network; the Columbia University Medical Center Institutional Review Board waived consent for adult donor hearts, given that consent for research was already documented by the New York Organ Donor Network and that tissue would otherwise have been discarded. No identifying information from these patients was collected.Myocardial biopsies were prospectively collected from four patient cohorts: A) adult subjects with no known cardiopulmonary disease , , (n = 5); B) pediatric subjects undergoing congenital cardiac surgery with normal RV size and function , (n = 3); C) pediatric subjects with worsening but hemodynamically stable LV failure [LV and right ventricle ], with biopsy collected at time of orthotopic heart transplant (OHT), (n = 7); and D) pediatric subjects with decompensated bi-ventricular failure on BiVAD support with biopsy collected at the time of OHT , (n = 3).Subjects with no known cardiopulmonary disease whose organs were listed but were unable to be placed at the time of organ recovery for heart transplantation and who consented to tissue for research purposes by the New York Organ Donor Network were included in this study from 2004 to 2006. Organs were unable to be placed primarily due to logistical and timing constraints and matching incompatibilities - no organ was rejected from transplantation due to depressed ventricular function. At the time of organ recovery, cardioplegia with Celsior solution was administered in the standard fashion. A section (40 mg) of the left ventricle (LV) apex was immediately obtained at the conclusion of cardioplegia perfusion and flash frozen in liquid nitrogen for analysis.Children with complex CHD requiring cardiac surgery, cardiomyopathy with LV failure requiring orthotopic heart transplantation (OHT), or biventricular heart failure necessitating BiVAD support prior to OHT were enrolled in this study from 2007–2010 at the Children's Hospital of New York, Presbyterian Hospital - Columbia Campus. In patients undergoing complex CHD surgery, a sample of right ventricular outflow tract (RVOT) was obtained and flash frozen in liquid nitrogen for analysis. The Thoratec CentriMag  continuous flow pump was implanted in all patients. In both LV failure and BiVAD patients, myocardial samples were obtained at the time of cardiac transplantation/BiVAD explantation after cardioplegia infusion, and subsequently flash frozen in liquid nitrogen for analysis. Trans-esophageal echocardiography was performed on all patients at the time of surgery. Ventricular dysfunction and size was graded on a scale of 1–4  and interpreted by a pediatric cardiology echocardiographer. This grading system was used to overcome the limitations of quantitative echocardiographic measurements of RV function and to provide a tiered, discrete valuation of ventricular function solely for the purposes of graphically illustrating the relationship of myostatin/IGF-1 levels to myocardial dysfunction. None of the pediatric echocardiographic readings provide a quantitative measure of RV function, although LVEF is universally given. However, we thought it was vitally important for this study to include an analysis of RV function. Since use of a continuous variable (EF) for the RV was thus not available, we chose to quantify ventricular function according to the following system.LVEF:Ejection Fraction    Grade  >50                  1 35–50                2 20–35                3 10–20                4RVEF:Echo Description                                 Grade  Normal function                                  1 Mild dysfunction                                 2 Mild dysfunction with mild dilation              2.5 Moderate dysfunction with mild dilation          3 Moderate dysfunction with moderate dilation      3.5 Severe dysfunction, severely dilated             4Cardiac biopsies obtained for Western blotting were snap-frozen in liquid nitrogen and prepared as previously described 2. For all analyses, a p value of less than 0.05 was considered statistically significant. All data were analyzed utilizing SPSS 11.5 .Continuous variables are expressed as mean ± standard error (SE) and were compared using independent two-tailed t-testing or Wilcoxon-Mann-Whitney non-parametric testing, and one-way ANOVA with post-hoc Bonferroni analysis, when necessary. Categorical variables were compared by χp<0.05). Pre-OHT/BiVAD LV function was poor in both OHT and BiVAD patients (Left ventricular ejection fraction (%): 26±7.5 and 18±4.3, respectively), but only BiVAD patients displayed severe RV dysfunction. RV function in OHT and RVOT was mildly abnormal. BiVAD patients were supported for a mean of 4.3±1.9 days prior to transplantation. All BiVAD patients were successfully bridged to transplantation.Demographic data for normal subjects and pediatric patients from which myocardial tissue samples were obtained are summarized in Myostatin ran at approximately 50 kDa, an apparent molecular weight that was somewhat higher than predicted, most likely due to glycosylation  [12]. An2 = 0.91, R2 = 0.91, respectively) (A link between myostatin and IGF-1 in the failing heart has been suggested in the literature ctively) .MEF-2 is a transcription factor that has been implicated in the regulation of myostatin expression To our knowledge, this is the first study investigating myostatin regulation in the pediatric heart, and our primary findings in this small cohort of patients are (i) myostatin expression is increased in compensated LV HF (LV-OHT) compared to paired normal RV control (RV-OHT) and unpaired normal RV control (RVOT), (ii) myostatin expression is increased in decompensated biventricular HF after mechanical unloading (BiVAD) compared to both compensated HF (OHT) and control (RVOT), (iii) the myostatin/IGF-1 ratio increases in correlation with the degree of ventricular dysfunction, and (iv) MEF-2 expression is increased in compensated LV HF (LV-OHT) vs. normal LV  and further increased in decompensated biventricular failure after mechanical unloading (BiVAD).mdx model of DMD accelerates the onset of systolic dysfunction and LV chamber dilatation The role of myostatin in HF has not yet been definitively determined It is interesting to note the much larger relative increase in myostatin after BiVAD support versus LVAD support et al found that myostatin is increased following cardiomyocyte stretch in culture and that this increase in expression is dependent upon IGF-1 secretion and subsequent signaling through the p38 pathway et alWe also examined the relationship between myostatin and IGF-1 in this study and found that the ratio of myostatin to IGF-1 increased as ventricular function decreased. A link between myostatin and IGF-1 in the heart has been previously suggested It is unclear at this point whether the increased myostatin to IGF-1 ratio causes or contributes to ventricular dysfunction in HF. It is known that decreased activity of the growth hormone (GH)/IGF-1 axis (low IGF-1 syndrome) is predictive of poorer outcomes and higher mortality in HF In summary, we have demonstrated for the first time that myostatin expression is increased in pediatric compensated LV failure and further increases in decompensated biventricular failure after mechanical support. In addition, we observed that the myostatin/IGF-1 ratio may increase as ventricular function decreases. Future investigation is needed to determine the effects of myostatin inhibition and overexpression in HF.