Transthoracic echocardiography (TTE) is a useful tool for minimally invasive hemodynamic monitoring in the ICU. Dynamic indices (such as the inferior vena cava distensibility index (dIVC)) can be used to predict fluid responsiveness in mechanically ventilated patients. Although quantitative use of the dIVC has been validated, the routinely used qualitative  approach had not been assessed before the present study.Qualitative and quantitative assessments of the dIVC were compared in a prospective, observational study. After operators with differing levels in critical care echocardiography had derived a qualitative dIVC, the last (expert) operator performed a standard, numeric measurement of the dIVC (referred to as the quantitative dIVC). Two groups of patients were separated into two groups: group (dIVC < 18%) and group (dIVC ≥ 18%).In total, 114 patients were assessed for inclusion, and 97 (63 men and 34 women) were included. The mean sensitivity and specificity values for qualitative assessment of the dIVC by an intensivist were 80.7% and 93.7%, respectively. A qualitative evaluation detected all quantitative dIVCs >40%. Most of the errors concerned quantitative dIVCs of between 15% and 30%. In the dIVC <18% group, two qualitative evaluation errors were noted for quantitative dIVCs of between 0 and 10%. The average of positive predictive values and negative predictive values for qualitative assessment of the dIVC by residents, intensivists and cardiologists were 83%, 83%, and 90%; and 92%, 94%, and 90%, respectively. The Fleiss kappa for all operators was estimated to be 0.68, corresponding to substantial agreement.The qualitative dIVC is a rather easy and reliable assessment for extreme numeric values. It has a gray zone between 15% and 30%. The highest and lowest limitations of the gray area are rather tedious to define.Despite reliability of the qualitative assessment when it comes to extreme to numerical values, the quantitative dIVC measurement must always be done within a hemodynamic assessment for intensive care patients. The qualitative approach can be easily integrated into a fast hemodynamic evaluation by using portable ultrasound scanner for out-of-hospital patients. The management of patients with acute circulatory failure requires knowledge of the preload dependence state. Dynamic indices predict the response to volume expansion with greater accuracy than do static indices. This assessment is very important because inadequate fluid replacement or inappropriate infusion of catecholamines can lead to significant adverse effects. Severalet al.[Several studies have demonstrated the acceptability of qualitative  measurement of the left ventricular ejection fraction when compared with quantitative reference measurements, 19. Simet al. validateet al.–23, the et al., 7. The The relevance and reproducibility of a qualitative approach for calculating the dIVC has not previously been established. We therefore sought to assess the accuracy of a qualitative approach of dIVC and compare it with that of the quantitative method. We also sought to evaluate the impact of the operator's level of experience on the accuracy of the qualitative approach.This was a prospective, observational study performed in a surgical ICU at a university hospital. The noninterventional study's objectives and data-collection procedures were approved by the Institutional Review Board (IRB) for human subjects at our hospital . Informed consent was waived because the IRB considered the protocol to be part of usual care in clinical practice.The main inclusion criteria were as follows: (a) patients undergoing TTE for hemodynamic assessment; (b) age older than 18 years; and (c) sedated and mechanically ventilated patients who were synchronized with the respirator . The main exclusion criteria were as follows: (a) patients with changes in hemodynamic status during the various measurement , and (b) poor visualization of the IVC by even the most experienced operator.n = 4), considered as operators with a basic level of experience (level 1) of critical care echocardiography (less than 30 TTEs), (b) two intensivists (n = 2) with an advanced level of experience (level 2) in critical care echocardiography, and (c) two cardiologists (n = 2) with high levels of expertise (level 3) in critical care echocardiography. The levels of echocardiography skills and knowledge were those described in the guidelines issued by the American College of Chest Physicians and the French Society of Intensive Care[The operators who performed a qualitative assessment of dIVC had various levels of experience and training in TTE: (a) four anesthesiology residents  just upstream of the junction of the hepatic veins, once the M-mode cursor was perpendicular to the IVC. The ultrasound system used was an EnVisor  with an S4-2 Hz probe. Operators performing echocardiographic examination of the IVC were blinded to the patient's fluid-responsiveness status. Each operator had to answer exactly three questions: Is the variation of dIVC greater than 18%, less than 18%, or not viewable?The dIVC was measured last by the most expert operator . The image was obtained as described earlier, and the dIVC was calculated according to the following equation: (maximum diameter on inspiration _ minimum diameter on expiration)/minimum diameter on expiration. The speed of the trace was 12.5 mm/sec.et al.[The quantitative reference cut-off value used for assessing preload dependence was 18%, in line with the study by Barbier et al.. Patientvariation) was expressed as a percentage and calculated according to the following equation: PPvariation = ((systolic blood pressure (SBP)max - diastolic blood pressure (DBP)max) - (SBPmin - DBPmin))/((SBPmax - DBPmax) + (SBPmin - DBPmin))/2).The respiratory pulse pressure variation  of the 114 patients were not included in the study. Hence, our analysis covered 97 patients . The reason for ICU admission was postcardiac surgery care in 75 (77.3%) cases, septic shock in 18 (18.6%) cases, and multiple trauma in four (4.1%) cases. The patients were separated into two subgroups on this basis: (a) quantitative dIVC <18%; (b) quantitative dIVC ≥18%.No differences were found between quantitative dIVC <18% and dIVC ≥18% groups in terms of demographic variables and severity scores (Table P = 0.04) and DBP (P = 0.03) values. The maximum and minimum IVC diameters were lower in responders (P < 0.01), and PPV was higher (P < 0.001).The main ventilator settings and hemodynamic parameters are summarized in Tables The sensibility, specificity, positive, and negative predictive values were similar in different groups of operators and are presented in Table The average sensitivity and specificity values for qualitative assessment of the dIVC by anesthesiologists (residents and intensivists) were 80.7% and 93.7%. The kappa coefficient for the entire group of operators was calculated to be 0.68, corresponding to substantial agreement. The kappa coefficients for each operator are presented in Table Qualitative dIVC assessment had a very low error rate for the 73 (75%) patients with quantitative values <15% and >30%. Unfortunately, the error rate was as high as 35% for quantitative values in the range 15% to 30%, which concerned 24 patients (25%) [The cut-off used for assessing preload dependence with quantitative dIVC was 18%: this is to 13%). For dIVThe quantitative dIVC requires less time with an evolutive ultrasonographic machine available in the intensive care units. The gain of accuracy of the quantitative dIVC measures has improved with the technique and can reduce its gray zone around 18%.Our study has several limitations.No fluid assessment was completed to find changes in qualitative dIVC or quantitative dIVC, nor in cardiac output. The qualitative dIVC was measured according to the hemodynamic status of patients when assessing different measures, nor was the study random, nor was it our main objective.Our failure rate for visualization of the IVC was 14.9%. This rate is close to the literature values, 30. HowGiven that 14.9% of patients were not evaluable and 20.6% (20 patients) are in the gray area of dIVC, between 15% and 30%, about 40% of patients are not evaluable by reliable visual methods. Nevertheless, a limit exists for all assessments preload dependency with the inferior vena cava, because these limits also apply to quantitative dIVC if we consider the "principle of the gray area".Although our qualitative assessment was performed by just eight operators with different levels of experience of TTE, the study involved a large enough number of patients to confirm the technique's utility under different load and volume-expansion conditions. However, the large number of measurements and the satisfactory correlations between qualitative and quantitative dIVC assessments by the various operators confirmed that it is possible to use the qualitative-technique assessment on a daily basis. Our least experienced operators (level 1) had performed an average of 30 TTE examinations. An operator must understand some basic technical details of TTE before he or she can perform a dIVC assessment, because it is not always easy to obtain a good view and identify the best measurement site. Validation of qualitative dIVC assessment by a larger number of operators would nevertheless be of value.The qualitative assessment of the dIVC has a gray zone between 15% and 30%. The sensitivity and specificity are good for values below 15% and above 30%, regardless of the operator's level of experience in ultrasound. Despite reliability of the qualitative assessment when it comes to extreme to numeric values, the quantitative dIVC measurement must always be done within a hemodynamic assessment for intensive care patients. The qualitative approach can be easily integrated into a fast hemodynamic evaluation by using a portable ultrasound scanner for out-of-hospital patients . Qualitative assessment of the dIVC has a gray zone between 15% and 30%, which should encourage the use of quantitative measurement of the dIVC in intensive care patients. The correlation between qualitative and quantitative dIVC was considered good regardless of the operator's level of experience in ultrasound. Qualitative dIVC assessment can easily take place in out of hospital FAST hemodynamic assessment, with a portable ultrasound scanner.


Microvascular injury is present in a large proportion of patients with ST-elevation myocardial infarction (STEMI) despite successful revascularization. Ticagrelor potentially mitigates this process by exerting additional adenosine-mediated effects. This study aims to determine whether ticagrelor is associated with a better microvascular function compared to prasugrel as maintenance therapy after STEMI. A total of 110 patients presenting with STEMI and additional intermediate stenosis in another coronary artery will be studied after successful percutaneous coronary intervention (PCI) of the infarct-related artery. Patients will be randomized to treatment with ticagrelor or prasugrel for 1 year. FFR-guided PCI of the non-infarct-related artery will be performed at 1 month. Microvascular function will be assessed by measurement of the index of microcirculatory resistance (IMR) in the infarct-related artery and non-infarct-related artery, immediately after primary PCI and after 1 month. The REDUCE-MVI study will establish whether ticagrelor as a maintenance therapy may improve microvascular function in patients after revascularized STEMI. Percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI) leads to an improved patency rate of the infarct-related artery, a lower incidence of heart failure, and ultimately an improved survival as compared to thrombolytic treatment . HoweverMVI can be visualized by non-invasive methods using cardiovascular magnetic resonance imaging (CMR) or measured by invasive methods such as intracoronary thermodilution . MVI as From the acute to late phase of a revascularized myocardial infarction, several mediators are thought to contribute to the development of MVI. These factors involve the appearance of intraluminal platelets, fibrin thrombi, and neutrophilic granulocytes, resulting in inflammatory cell plugging, formation of microthrombi, endothelial activation and injury, and finally MVI. Vasoconstriction follows as a result of endothelial dysfunction with decreased levels of nitric oxide and increased levels of endothelin-1. Furthermore, the imbalance in coagulation factors and influx of inflammatory cells can cause vascular leakage and hemorrhage , 7. Aden12-receptor antagonists ticagrelor and prasugrel, in addition to aspirin, are the recommended antiplatelet drugs according to European and American guidelines [Currently, in patients with STEMI, the P2Yidelines , 11. Theidelines . Interesidelines –17. TherThe Reducing Micro Vascular dysfunction In revascularized ST-elevation myocardial infarction patients by off-target properties of ticagrelor (REDUCE-MVI) study is a multicenter trial with a prospective, randomized, open-label, blinded-endpoint (PROBE) study design. Current participating centers are the VU University Medical Center , the Erasmus Medical Center , the Medisch Spectrum Twente , and the Hospital Clínico San Carlos . A flow chart of the study design is shown in Fig. On hospital arrival, patients presenting with an acute STEMI will be screened for participation in the study according to the inclusion and exclusion criteria Table . ST-elev12 inhibitor ticagrelor in the ambulance before primary PCI with a third-generation drug-eluting stent (DES) (standard of care in participating centers). After successful primary PCI, myocardial tissue perfusion of the infarct-related area will be assessed by determining the myocardial blush grade [PCI will be performed according to standard procedures and is left to the discretion of the operator. All patients will receive a loading dose of heparin, aspirin, and the P2Ysh grade .After 1 month, patients will undergo clinically indicated FFR-guided PCI of the intermediate lesion in the non-infarct-related artery.Patients will be randomly assigned to use either ticagrelor 90 mg BID or prasugrel 10 mg SID as a maintenance therapy continued for 1 year according to current international guidelines . ConcomiThe primary objective of this study is to determine whether ticagrelor at treatment steady-state in revascularized STEMI patients is associated with an improved microvascular function as measured with IMR, compared to prasugrel. Both treatment groups are subjected to the same measurements at three time points. The function of the coronary microcirculation is considered as primary endpoint which will be assessed by determining the index of the microcirculatory resistance (IMR) . MicrociIMR in the infarct-related artery will be measured after 1 month and compared to IMR immediately after primary PCI. Secondly, IMR in the non-infarct-related artery will be determined after 1 month and compared to measurements at baseline Fig. .Fig. 2PrBy using a coronary pressure and temperature-sensitive guidewire  and modified software, the transit time of room-temperature saline injected in a coronary artery can be determined. After an intracoronary injection of 200 mcg nitroglycerine to establish epicardial coronary vasodilatation, the guidewire is calibrated outside the body, equalized with aortic pressure at the ostium of the guide catheter, and then advanced into the distal third of the artery and distal to the stent in the infarct-related artery. The mean transit time at baseline is obtained by administering three times 3 mL of intracoronary saline. Thereafter, hyperemia is induced by administering adenosine at 140 mcg/kg per minute intravenously and measurement of mean transit time is repeated. Aortic and distal coronary pressures are recorded simultaneously. The distal coronary pressure divided by the inverse of the hyperemic mean transit time then provides the IMR. This calculation will be performed by independent and blinded analysts in a core laboratory.Optical coherence tomography (OCT) will be performed at 1 month with a Dragonfly™ OCT catheter  using a motorized pullback device. OCT pullbacks will be performed at a speed of 20 mm/s in the infarct-related and non-infarct-related arteries, using in general a contrast flush rate of 3 mL/s in the right coronary artery and 4 mL/s in the left coronary artery. The occurrence of subclinical stent thrombus, stent malposition, and edge dissections will be assessed. All acquired images are sent to a core laboratory for blinded evaluation  using a standardized protocol.The peripheral endothelial function will be measured within 24 h after primary PCI, at 1 month, and 1 year follow-up.®  is a validated device indicated for non-invasive endothelial and microvascular function assessment [® will be used to measure the finger arterial pulsatile volume changes that indicate changes in vascular tone, by modified plethysmographic probes placed on the index finger of each hand [EndoPATsessment –22. Endoach hand . The meaThe reactive hyperemia index (RHI) and its natural logarithm are then calculated as the ratio of the magnitude of the average post-occlusive pulse volume amplitude to the average pre-occlusive pulse volume amplitude, corrected for baseline vascular tone.After 1 month and optionally at baseline (day 2–7), CMR will be performed with a 1.5 or 3.0 Tesla scanner using a phased array cardiac receiver coil. All images are ECG-gated and acquired during mild end-expiration breath-holding. Cine long- and short-axis slices are obtained to examine regional and global left ventricular function, volumes, and ejection fraction. Evaluation of myocardial ischemia will be assessed with first-pass perfusion imaging of a gadolinium-based contrast agent during the administration of 140 mcg/kg per minute of adenosine intravenously. Finally, late gadolinium-enhanced (LGE) images are acquired 10 min after perfusion imaging, to identify the size and extent of myocardial infarction and, in addition, the presence and extent of MVI. When performed at baseline, T2-weighted imaging will be acquired in short-axis planes for the detection of intramyocardial hemorrhage and infarct-related edema. All CMR analyses will be performed in a core laboratory by blinded observers using a standardized protocol.12 inhibition levels will be assessed by VerifyNow testing . The effect of ticagrelor on inflammatory markers and cells, such as cell adhesion molecules and monocytes, will be studied concomitantly. In addition, the level of biochemical markers for endothelial function, like asymmetrical dimethylarginine, will be measured, which allows linking these results to the microvascular function.Blood samples for laboratory testing will be drawn at baseline and at 1 month and 1 year follow-up according to standard procedures. The testing includes standard biochemistry and hematology tests . Furthermore, extra blood samples will be collected and stored at −80 °C. At the end of the study, all samples will be analyzed by the laboratory at the VU University Medical Center. The plasma levels of ticagrelor will be examined as well, and P2YAdverse events (AEs) are evaluated and registered during index hospitalization and at 1 month and 1 year follow-up. AEs occurring in external participating centers will be reported to the sponsor. A serious adverse event (SAE) is a severe undesirable event in which there was no necessarily causality with the study. The relationship of SAEs to study treatment or procedures will be assessed by the investigators and communicated to AstraZeneca.As a safety measure, bleeding complications will be monitored during the entire study period, categorized to the most recent criteria , 47 subjects in each group are required. Assuming a loss of follow-up of maximally 15 %, it will be necessary to include a total of 110 patients in the study. After 50 % inclusion (n = 55) with complete 30-day follow-up, an interim analysis will be performed to verify the assumed standard deviation and, if necessary, we might adjust the total sample size needed to achieve an adequate power.The study is powered using a superiority design with the null hypothesis that IMR will be significantly improved in the ticagrelor group in comparison to the prasugrel group. A difference of IMR means of 7 at 1 month follow-up between the two treatment groups, with a standard deviation of 12, is expected . To be aOptimal therapy of STEMI requires both treatment of the macrovasculature and the microvasculature. Over the years, treatment of the macrovasculature has improved notably. Due to refined stent designs and more biocompatible polymers on DESs, the prevalence of acute stent thrombosis and restenosis has been reduced significantly. However, inadequate myocardial perfusion after restoration of the epicardial blood flow by primary PCI is present in a large proportion of STEMI patients. Nearly 50 % of the final myocardial infarct size is due to myocardial reperfusion injury, and thus, a logical target for reducing myocardial infarct size, thereby maximizing the benefits of reperfusion .12-receptor antagonist and aspirin. According to current ESC and ACCF/AHA guidelines, both ticagrelor and prasugrel have a class 1B recommendation for use after STEMI [The cornerstone of treatment of patients after STEMI is antithrombotic therapy with a P2Yer STEMI , 11. Boter STEMI , 29. Witer STEMI .12-receptor antagonists, do not mediate such conservation of the plasma adenosine concentration [It has been shown that ticagrelor, besides its antiplatelet effects, also has the potency of increasing the plasma concentration of endogenous adenosine in patients with acute coronary syndromes. Adenosine is produced particularly after tissue damage by hypoxia, and ticagrelor has the ability to inhibit intracellular uptake through the adenosine equilibrative nucleoside transporter 1 (ENT1). Prasugrel and clopidogrel, two other P2Yntration , 16. ThiThere is evidence that elevations of adenosine reduce the inflammatory response in the different phases after revascularized myocardial infarction, by interfering with the production of inflammatory mediators and oxygen species and neutrophil trafficking , 9.In the acute phase of myocardial infarction, myocardial damage is enhanced by the formation of microthrombi as a result of a hypercoagulable state and by inflammatory cell clogging of the intramyocardial microvasculature. In the early phase (hours to days), infiltrating cells further amplify damage, as an influx of blood-borne inflammatory cells leads to production of inflammatory mediators and tissue-destructive agents such as metalloproteinases . In the In these ways, adenosine might reduce ischemia and reperfusion injury, preserving microvascular function. This might be most important for patients with STEMI, as coronary MVI and dysfunction appear to be most pronounced in this patient group, compared to patients with non-ST-elevation acute coronary syndrome .In the REDUCE-MVI study, we aim to investigate the potential adenosine-mediated effects of ticagrelor with several outcome parameters, especially IMR, to determine the effect on coronary microvascular function.In the coming years, more insight into the biochemical mechanisms involved in STEMI may be expected, which may hopefully lead to the development of more specific drugs for microvascular preservation. Along this line, the REDUCE-MVI study is focused in more detail on current therapeutic options to retain microvascular integrity and function in patients with STEMI.


Cardiovascular magnetic resonance (CMR) of ventricular structure and function is widely performed using cine balanced steady state free precession (bSSFP) MRI. The bSSFP signal of myocardium is weighted by magnetization transfer (MT) and T1/T2-relaxation times. In edematous and fibrotic tissues, increased T2 and reduced MT lead to increased signal intensity on images acquired with high excitation flip angles. We hypothesized that acquisition of two differentially MT-weighted bSSFP images (termed 2-point bSSFP) can identify tissue that would enhance with gadolinium similar to standard of care late gadolinium enhancement (LGE).o were calculated as (S45-S5)/S5*100 (%), where Sflip_angle is the voxel signal intensity.Cine bSSFP images (flip angles of 5° and 45°) and native-T1 and T2 maps were acquired in one mid-ventricular slice in 47 patients referred for CMR and 10 healthy controls. Afterwards, LGE images and post-contrast T1 maps were acquired and gadolinium partition coefficient (GPC) was calculated. Maps of ΔS/So, native-T1, T2, and GPC were heightened (p < 0.05 vs. non-enhanced tissues). ΔS/So, native-T1, and T2 all demonstrated association with GPC, however the association was strongest for ΔS/So. Bland-Altman analysis revealed a slight bias towards larger volume of enhancement with ΔS/So compared to LGE, and similar transmurality. Subjective analysis with 2-blinded expert readers revealed agreement between ΔS/So and LGE of 73.4 %, with false positive detection of 16.7 % and false negative detection of 15.2 %.Twenty three patients demonstrated areas of myocardial hyper-enhancement with LGE. In enhanced regions, ΔS/SGadolinium free 2-point bSSFP identified tissue that enhances at LGE with strong association to GPC. Our results suggest that with further development, MT-weighted CMR could be used similar to LGE for diagnostic imaging.The online version of this article (doi:10.1186/s12968-015-0194-1) contains supplementary material, which is available to authorized users. Cardiovascular magnetic resonance (CMR) has become a reference standard modality to image ventricular structure, contractile function, and perfusion . CombineBoth edematous and fibrotic myocardium are characterized by an increased extracellular volume fraction, which results in lengthened native-T1 and T2-relaxation times compared to healthy myocardium. These changes have been used to identify edema in acute MI , 8 and fWe hypothesized that acquisition of bSSFP cine image sets with different MT-weighting (termed 2-point bSSFP) could combine the changes in signal intensity due to both lengthened T1/T2-relaxation and reduced MT to identify tissue that would enhance with gadolinium in close agreement to LGE. We compared tissue characterization with 2-point bSSFP, native-T1 and T2-mapping to LGE in 47 patients referred for CMR at our institution. Our results demonstrate robust agreement between gadolinium free 2-point bSSFP imaging and standard of care LGE, with a strong association between 2-point bSSFP and GPC.Fifty non-consecutive patients referred for clinically indicated CMR with gadolinium contrast were prospectively enrolled, however 3 were excluded due to inability to maintain breath-holds. All patients referred for CMR with gadolinium contrast at our institution over a six month period were approached for study participation, with the forty seven included in the study representing those that consented to participate. Afterwards, ten healthy age-matched controls were recruited but did not receive gadolinium. The research protocol was approved by our institutional review board (IRB 12-0795-F3R) and informed consent was obtained from all subjects for participation and publication of findings. Demographic characteristics are summarized in Table CMR was performed on a 1.5 T Siemens MAGNETOM Aera scanner  using an 18 channel body coil and 12 channel spine coil. A short-axis stack of bSSFP cine images were obtained with prospective ECG triggering to cover the entire heart , from which one mid-ventricular slice was identified for further imaging. The signal intensity of bSSFP images acquired with high excitation flip angles and short repetition times is heavily weighted by MT, T1 and T2, while identical images acquired with low flip angles reflect proton density weighting with minimal contributions from MT. In the identified slice, pairs of bSSFP cine images were acquired with excitation flip angles of 5° (proton density reference) and 45°  during end-expiratory breath-holds. Native myocardial T1-relaxation times were assessed using a modified Look-Locker imaging (MOLLI) sequence (5(3)3, TE: 1.1 ms, TR: 2.7 ms, flip angle: 35°, bandwidth: 1085Hz, field of view: 272x 272 mm, slice thickness: 8 mm, 256 matrix with 66 % phase resolution, partial Fourier transform 7/8, GRAPPA 2). T2-relaxation times were assessed using a gradient echo readout  in the same short axis slice during diastasis. Afterwards, gadolinium (0.2 mmol/kg Gd-DTPA) was administered intravenously as a bolus (rates ranged from 2 ml/s to 5 ml/s) and after 15 min LGE images were obtained using segmented gradient recalled echo inversion recovery  with inversion time set to optimally null the myocardium. Finally, post-contrast MOLLI (4(1)3(1)2, TE:1.1 ms, TR:2.7 ms, flip angle: 35°, field of view: 272 x 272 mm, GRAPPA 2) images were obtained in the same slice position as pre-contrast images. Normal volunteers only underwent non-contrast portions of the protocol.o)i = [(S45-S5)/S5]i, where S45 and S5 represent the signal intensity for 45° and 5° excitations respectively for each cardiac phase (i). For each patient ΔS/So maps from three diastolic phases without cardiac motion were averaged together to reduce random noise. Maps of GPC were calculated as GPC =  from reconstructed T1-maps.Maps of T1 and T2-relaxation times were automatically reconstructed after motion correction using non-rigid body correction. The reproducibility of breath-hold position and the degree of mis-alignment between 5° and 45° scans was assessed via calculation of the DICE similarity coefficient for both complete images and segmented images in which only the heart was included. 2-point bSSFP data was analyzed by calculating the normalized change in signal between images as  used a custom designed MATLAB script to segment the myocardium and define a non-enhanced region of interest (ROI) in each LGE image. Myocardial voxels with signal intensity greater than 5 standard deviations (SD) above the mean of the defined ROI were classified as enhanced at LGE. Maps defining LGE-enhanced and non-enhanced regions were saved, transmitted to MHV, and used to segment ΔS/So, a threshold value of 197 %  was applied and used to calculate the fraction of myocardial voxels above the threshold. Transmurality was calculated as the percentage of enhancement along the radial direction at the center of the area of enhancement for LGE and ΔS/So maps.In data acquired from patients demonstrating enhancement at LGE, the enhanced area was calculated as the percentage of all myocardial voxels classified within the enhanced ROI. To calculate the enhanced area from maps of ΔS/So and native-T1 in Figs. Figures were prepared using a median filter with a 3x2 kernel  of enhancement, and to delineate the extent of enhancement on each image.Subjective assessment of 2-point bSSFP in comparison to LGE was performed by two blinded readers with 1 and over 10 years experience. All ΔS/St-test. Statistical significance in pairwise comparisons was defined by a p-value < 0.05 divided by the number of comparisons to control Type I testing error through Bonferroni adjustment. Otherwise, a p-value < 0.05 defined statistical significance.Numeric data are summarized as mean ± SD. For outcome variables we used Version 9.3 of SAS software  to fit a linear mixed model comparing mean levels across four groups of heart tissue: healthy controls (Group I), patients without LGE-enhancement in the imaged slice (Group II), non-enhanced regions of interest from patients with LGE-enhancement (Group III), and enhanced regions of interest from patients with LGE-enhancement (Group IV). We included random effects for subjects to account for correlations between measurements on non-enhanced and enhanced tissue from the same patient with LGE-enhancement. Linear contrasts were used for pairwise comparisons. Demographic variables were analyzed using SPSS . The Shapiro-Wilk method was used to test normality of numeric data. Age, body mass index (BMI), and race were compared across all participants using the Kruskal-Wallis method. Fisher’s exact tests were used to compare gender across all participants and CMR diagnosis between the two patient groups. Differences in EF were compared via Mann–Whitney and EDV was analyzed by student’s p < 0.001 for all).Amongst 23 patients who demonstrated LGE-enhancement in the imaged slice, EDV trended higher and EF trended lower compared to patients who did not demonstrate LGE-enhancement Table . There wo in a healthy control subject and a patient without LGE-enhancement revealed uniformly low ΔS/So values across both hearts  compared to all non-enhanced regions (Groups II and III) and healthy controls  in absolute terms. Segmentation of the heart into twelve equal circumferentially spaced sectors revealed moderately lower average ΔS/So values (118.8 ± 14.7 (%)) in the anterior-lateral wall compared to the rest of the myocardium. Additionally, GPC was significantly elevated in LGE-enhanced regions  and healthy controls  with the percent of myocardium classified as enhanced at LGE , and Bland-Altman analysis revealed a coefficient of variation of 0.0875 , however LGE-enhancement was present in other slices. Additionally, limitations on T1 and T2-mapping protocols on our scanner resulted in acquisition of bSSFP images at slightly higher spatial resolution. Consequently, partial volume error is more likely to influence T2 maps, and to a lesser extent T1 maps, than 2-point bSSFP results. Care was taken to adjust boundaries to exclude border pixels affected by partial volume artifacts, however registration of pre and post gadolinium maps was not performed. The sensitivity to B1 inhomogeneity remains a significant concern in cine bSSFP, particularly at higher flip angles. We simulated the bSSFP signal using a range of myocardial relaxation times and excitation flip angles. Based on the results of our simulation, and prior evidence that MT is maximal and constant above excitation flip angles of 30° , we chos2-point bSSFP utilizes endogenous contrast mechanisms for gadolinium-free CMR imaging. In this study, we demonstrated across a range of patients strong association between 2-point bSSFP and standard of care LGE-CMR. Importantly, since MT-contrast is an endogenous mechanism, the sensitivity to changes in MT-weighting increases with spatial resolution. In addition, MT-contrast can be further increased with MT-preparation schemes not used in this initial study. In contrast, differences in native-T1 between healthy and diseased tissue can not be further increased without increasing the magnetic field strength. With further development, MT-weighted CMR could potentially enable diagnostic imaging similar to LGE CMR without the use of gadolinium.


Sleep disordered breathing is well described in adults with heart failure but not in pediatric population. We describe a 13-year-old Caucasian male with severe heart failure related to dilated cardiomyopathy who demonstrated polysomnographic features of Cheyne-Stokes respiration, which completely resolved following cardiac transplantation. Cheyne-Stokes respiration in children with advanced heart failure and its resolution after heart transplant can be observed similar to adults. In adults with heart failure (HF), Cheyne-Stokes respiration (CSR) is found to be a common polysomnographic (PSG) finding . CSR is The patient, a 13-year-old Caucasian male, presented with DCM and, after progressive deterioration of his ejection fraction, eventually required admission to the hospital for progressive HF. His symptoms were increasing daytime tiredness and lethargy as well as history of syncopal episodes and increased dyspnea on effort which all were attributed to the severe heart failure. His symptoms were New York Heart Association (NYHA) class III. Specifically, echocardiography showed deterioration of his cardiac function (decreased left ventricular ejection fraction [LVEF] from 30% to 9% over a two-month period). Medical therapy had included Digoxin, Carvedilol, Ramipril, and Spironolactone. He underwent a standard PSG according to international guidelines at the time of admission that was part of a prospective observational study to describe sleep disordered breathing (SDB) in children with known cardiomyopathy, the group data of which have been published elsewhere . SignifiFour weeks after the baseline PSG, and before any treatment was initiated specifically for CSR, the patient underwent an orthotropic heart transplant. Following this, he was able to recover to normal NYHA status, with no symptoms, and normal cardiac function (LVEF was 61%). A follow-up baseline PSG was done 3 months after heart transplantation to reevaluate his sleep related breathing. At this time point, he was clinically stable. His medications at this time included Prednisone, Mycophenolate Mofetil, and Tacrolimus. His repeat PSG showed that his breathing pattern had normalized with no further evidence of CSR. In adults, CSR has been described in detail in patients with HF , with re2 falls below the apnea threshold. CSR is present when central apneas occur in cyclical fashion. The phenomenon is thought to be related to respiratory control system instability as well as a delayed circulatory time in association with low cardiac output in HF [2 which drops to a level close to the apnea threshold. Since patients with HF and CSR have lower PaCO2 than those without CSR during sleep [Central apneas during sleep occur when PaCOut in HF . This ocut in HF . The patng sleep , the preTo date, there are two cases of children in HF with description of CSR , 6. HochIn children, cardiomyopathy is a rare but serious and life-threatening condition with an annual incidence of 1.1–1.2/100,000. Dilated cardiomyopathy is the dominant phenotype, with two-thirds of all cases remaining idiopathic after diagnostic evaluation. The prognosis of DCM in children is guarded with increased morbidity and mortality, and currently 32–46% of patients with DCM will either receive a heart transplant or die within five years of diagnosis. Our patient had severe DCM with severely impaired cardiac function and he received an urgent heart transplant because of his deteriorating condition.Several adult case reports and series have shown resolution and improvement of CSR in patients with HF after heart transplant , occurriIn conclusion CSR can be present in children with advanced heart failure. We speculate that it may contribute to the symptom progression in these patients and may be a risk factor for death for that reason, although there are insufficient cases to determine this at present. Resolution of CSR after pediatric heart transplant would be expected assuming no other contributory factors are identified. Prospective evaluation of patients for the presence of sleep related disordered breathing appears justified, even in the pediatric age group, when advanced heart failure is identified.


Enhanced external counterpulsation (EECP) is currently applied for treating coronary artery disease (CAD) patients. However, the mechanism(s) by which EECP ameliorates angina pectoris and long-term left ventricular function remain largely unknown. The aim of this study will be to assess whether EECP significantly affects myocardial perfusion in CAD patients through a systematic review and meta-analysis of the available literature.2 index. Publication bias was assessed through visual inspection of the funnel plot as well as Begg’s and Egger’s testing.MEDLINE, EMBASE, and Cochrane CENTRAL databases were searched for prospective studies on CAD patients that underwent EECP and reported myocardial perfusion data pre- and post-EECP. The impact of EECP was assessed based on the weighted mean difference (WMD) in myocardial perfusion from pre-EECP to post-EECP. Statistical heterogeneity was assessed by the Ip = 0.049). A random effects analysis was applied on account of significant heterogeneity . There was no evidence of significant publication bias .Standard EECP therapy  significantly increased myocardial perfusion in CAD patients (pooled WMD: -0.19, 95% CI: -0.38 to 0.00, Standard EECP therapy significantly increases myocardial perfusion in CAD patients. This study’s findings support the continued use of standard EECP therapy in CAD patients and provides one putative physiological mechanism to help explain the improvements in angina pectoris and long-term left ventricular function observed in CAD patients after EECP therapy. Enhanced external counterpulsation (EECP) is an outpatient coronary artery disease (CAD) therapy that involves the cyclical inflation/deflation of cuffs wrapped around the lower extremities . EECP isDespite these favorable findings supporting the clinical application of EECP in CAD patients, the mechanism(s) by which EECP ameliorates angina pectoris and long-term left ventricular function remain largely unknown. One hypothesis is that EECP promotes coronary blood flow and enhances coronary perfusion pressure . HoweverThis meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines  8]..8].We searched MEDLINE, EMBASE, and Cochrane CENTRAL databases from inception until May 2015 for relevant studies using the following key search terms:  AND perfusion. In addition, a manual search of relevant review articles were screened for additional records. The literature search was limited to human clinical trials reported in English.Two authors independently selected studies for inclusion with disagreements resolved by discussion and consensus. Studies were included for meta-analysis if they had a prospective design, included patients with a diagnosis of CAD that underwent EECP, and reported myocardial perfusion data pre- and post-EECP. According to patient selection criteria elaborated by early EECP research , CAD wasThe following data were independently extracted from the studies by two authors through the use of a standardized data abstraction sheet with disagreements resolved by discussion and consensus: first author’s name, year of publication, country of study, study design, patient selection criteria, study sample size, protocol and duration of EECP therapy, method of measuring myocardial perfusion and/or intracoronary pressure, data collection time points (pre- and post-EECP), and reported data on changes from baseline in one of two outcomes: (i) myocardial perfusion or coronary flow and/or (ii) intracoronary pressure.Two authors independently assessed study quality with disagreements resolved by discussion and consensus. The methodological quality of the included studies was evaluated using the Newcastle-Ottawa scale (NOS) for prospective cohort studies . Study q2 index with significant heterogeneity defined as an I2 value of greater than 50% and a p-value of less than 0.05 [Based on the available evidence, only one outcome—myocardial perfusion or coronary flow–was amenable to meta-analysis. All statistical analyses were performed using RevMan 5.0 (Cochrane Collaboration). Statistical heterogeneity was assessed by the Ihan 0.05 . A randohan 0.05 . The imphan 0.05 .The flowchart of study selection is provided in p = 0.049; 2 = 89.1%, p = 0.000; p = 0.091; Egger’s p = 0.282).Based on the available evidence, only one outcome—myocardial perfusion or coronary flow–was amenable to meta-analysis. The pre- and post-EECP myocardial perfusion values from the included studies are listed in Here, we assessed whether EECP significantly affects myocardial perfusion in CAD patients through a systematic review and meta-analysis of the available literature. We found that standard EECP therapy  significantly increased myocardial perfusion in CAD patients. This study’s findings support the continued use of standard EECP therapy in CAD patients and provides one putative physiological mechanism to help explain the improvements in angina pectoris and long-term left ventricular function observed in CAD patients after EECP therapy.Standard EECP therapy is based on a biomechanical device consisting of three basic components: a set of cuffs, an air compressor/pump, and a computer system . InitialWith specific respect to myocardial perfusion, our findings validate Michaels 2002’s Doppler and angiographic data that showed a 150% increase in coronary flow velocity as well as a 28% increase in coronary flow post-EECP , 20. MecThere are several limitations to this study. First, the study sample size of this meta-analysis was rather limited; thus, more clinical trials that measure myocardial perfusion (as well as intracoronary pressure) before and after EECP are needed. Second, the studies included in this meta-analysis employed a variety of methods for measuring myocardial perfusion, which may have affected the results. Third, one included study (Michaels 2002 ) compareIn conclusion, standard EECP therapy significantly increases myocardial perfusion in CAD patients. This study’s findings support the continued use of standard EECP therapy in CAD patients and provides one possible physiological mechanism to help explain the improvements in angina pectoris and long-term left ventricular function observed in CAD patients after EECP therapy.S1 Fig(DOC)Click here for additional data file.


A precise understanding of the anatomical structures of the heart and great vessels is essential for surgical planning in order to avoid unexpected findings. Rapid prototyping techniques are used to print three-dimensional (3D) replicas of patients' cardiovascular anatomy based on 3D clinical images such as MRI. The purpose of this study is to explore the use of 3D patient-specific cardiovascular models using rapid prototyping techniques to improve surgical planning in patients with complex congenital heart disease.This European prospective multicenter study included 8 patients with complex congenital heart diseases Figure . MagnetiThe Bland-Altman analysis showed accurate agreement in the diameter between medical images and 3D-models (-0.12±1.40 mm, mean bias ± standard deviation, Figure 3D-printed cardiovascular models accurately replicate the patient's anatomy and are extremely helpful for planning surgery in complex congenital heart disease. They may potentially reduce operative time and morbi-mortality.This research has been co-financed by Institute of Health Carlos III - FIS research grant number PI13/02319 from the Spanish Ministry of Science and Innovation.


Becker muscular dystrophy (BMD) is a severe genetic disease caused by an X-linked recessive mutation leading to reduced/abnormal dystrophin, resulting in a peripheral myopathy and a cardiomyopathy (CM). The purpose of this study is to evaluate the myocardial structure and function in BMD.From April 2012 to May 2014, 84 consecutive patients  with Becker muscular dystrophy (BMD) and 12 control subjects underwent cardiac magnetic imaging (MRI) on a 3-T clinical scanner . T1 maps and apparent extracellular volume fraction (appECV) pre- and post-Gd-DOTA injection was performed with a prototype modified Look-Locker sequence . T2 maps were generated with a T2 prepared TrueFISP sequence acquired with 3 preparation times . Late Gadolinium enhancement (LGE), T1, T2, appECV were assessed according to the classification of the AHA segmentation.t test for paired data. The abnormality cut-off values of GdT1 and T2 in the control group were respectively 400 ms and 53 ms. Combining both Gd T1 and T2 data , both fibrosis and inflammation in 1,2% vs 0.6 % (decreased T1 and increased T2).Mean left ventricular (LV) ejection fraction was 61±12% (range: 23-87 %), LV end-diastolic volume was 68±26 ml/m2 (range: 32-185 ml/m2) and LV mass 76±17 g/m2 (range: 48-122 g/m2). The values of native T1, GdT1, T2 and appECV of the LW l and the septum are summarized in table The LGE patterns are different in primitive CM and BMD: in primitive CM, LGE is usually mid-parietal and circumferential; in BMD, it is mainly lateral and sub-epicardial. Relaxometry data demonstrate that the main lesions are inflammatory and fibrotic. The coexistence of both inflammation and fibrosis is uncommon in the same segments. T2 mapping is a useful tool to differentiate fibrosis from both fibrosis and edema. Becker cardiomyopathy may be considered as a "chronic active genetic myocarditis". Further clinical and MRI investigations must explore if the relaxometry data may help to predict long-term survival in Becker dystrophy.N/A.


In this study, we perform a comprehensive comparison of global and regional strain in both the circumferential (εcc) and longitudinal (εL) dimensions to conventional SV hearts and normal hearts.Rarely, patients with normally sized RV and LV will undergo total cavopulmonary connection (TCPC) due to the complexity of their intracardiac anatomy giving them a dual ventricle (DV) for a single cardiac output. The ventricular function in this unique physiology compared to SRV, SLV and normal hearts remains poorly understood, with few studies performedcc and εL strain,Global εcc-free, εL-free) and septum ,Regional circumferential and longitudinal strains at free wall , SLV and SRV after TCPC, to compare:We performed a prospective analysis of 23 subjects .cc; and b) Fast-Strain Encoded (fSENC) images: Used for generating εL.Strain information was acquired at three short axis slices at basal, mid-cavity, and apical locations in all 123 subjects in a 1.5T MRI scanner (Philips Acheiva) using: a) Complementary Spatial Modulation of Magnetization (CSPAMM) images: Used for generating εcc and εL were calculated from SAX slices using DiagnosoftTM. The ventricular regions at each slice were assigned based upon the AHA 16 segment model  Compared to normals, there is a significant reduction in global εents fig .Figure 2L in mid-ventricular and apical locations of DV patients.2.) Compared to normals, there is a significant reduction in global εcc of the LV of DV patients consistently lower than SLV for global and regional calculations.3.) The εcc-free was higher in the RV (75 +/- 42%), with the εL-free being higher in the LV (25 +/- 10%).4.) In the same DV patient at the basal location, the εL progressed from base to apex in all groups.5.) Global εStrain values of the RV and LV in DV patients demonstrate significant differences compared to normal subjects. Additionally, the LV of DV patients had lower strain values than the SLV patients. The differences in the RV and LV within the same DV patient suggest inherent differences in ventricular biomechanics in this unique physiology. The shared workload of the LV and RV for a single cardiac output may contribute to their lower strain values.


The magnetization trajectory was simulated to identify sources of T1ρ error. To limit motion artifacts, an optical flow-based image registration method was used to align T1ρ images. The reproducibility and accuracy of these methods was assessed in phantoms and 10 healthy subjects. Results are shown in 1 patient with pre-ventricular contractions (PVCs), 1 patient with chronic myocardial infarction (MI) and 2 patients with hypertrophic cardiomyopathy (HCM).We developed a breath-held T1ρ images in subjects, as determined by the increase in Dice Score Coefficient (DSC) from 0.76 to 0.88. T1ρ reproducibility was high  = 0.85–0.97). Mean myocardial T1ρ value in healthy subjects was 63.5 ± 4.6 msec. There was good correspondence between late-gadolinium enhanced (LGE) MRI and increased T1ρ relaxation times in patients.In phantoms, the mean bias was 1.0 ± 2.7 msec (100 msec phantom) and 0.9 ± 0.9 msec (60 msec phantom) at 60 bpm and 2.2 ± 3.2 msec (100 msec) and 1.4 ± 0.9 msec (60 msec) at 80 bpm. The coefficient of variation (COV) was 2.2 (100 msec) and 1.3 (60 msec) at 60 bpm and 2.6 (100 msec) and 1.4 (60 msec) at 80 bpm. Motion correction improved the alignment of T1ρ mapping in a breath-hold with good accuracy and precision.Single-shot, motion corrected, spin echo, spin lock MRI permits 2D T In vivo myocardial T1ρ mapping has detected relaxation time changes that correlate with histologically-confirmed scar in animal models of ischemic heart disease T. Simulations were performed in Matlab .Simulations were performed to test the magnetization response to pulse sequence parameters. The time-dependent magnetization was solved using piecewise, time-independent matrix solution to the Bloch equations M(t)=eLt1ρ MRI pulse sequences were determined in phantoms and human subjects. A phantom was prepared with multiple known nuclear relaxation properties, as determined by the reference T1ρ sequence, and differences between measured and true T1ρ relaxation times were quantified. The phantom contained 8 cylindrical samples prepared with solutions of H2O and MnCl2 in concentrations of 0.002, 0.004, 0.006, 0.008, 0.010, 0.012, 0.015, 0.017% solutions, providing a range of T1ρ relaxation times that would be expected in vivo. Mean bias was analyzed for two phantoms with relaxation times similar to normal myocardium  and scar tissue . Scan parameters were the same as in the previous section in a single slice intersecting all phantoms and with TSL = 50, 42, 34, 26, 18, 10, 2 msec.The accuracy and precision of different T1ρ images were acquired in 10 normal subjects  without a previous history of cardiovascular events, 1 patient with chronic MI, 1 patient with PVCs, and 2 patients with HCM on a 1.5 T whole-body MRI system  at the Hospital of the University of Pennsylvania. The University of Pennsylvania Institutional Review Board approved this study and all subjects gave written informed consent to participate. 5 of the subjects underwent 3 MRI scans to assess the reproducibility of T1ρ maps.T1ρ-weighted images were acquired, during end-systole and end-expiration, to reduce the effects of cardiac and respiratory motion. The end-systolic cardiac phase was determined by first examining the cardiac motion on cine-SSFP short-axis images and then adjusting the beginning of spatial encoding with the period of maximum myocardial wall thickness. To further reduce respiratory motion artifacts, all T1ρ-weighted images were acquired within a single end-expiratory breath-hold using the same acquisition parameters as in the phantom experiments, and with flip angle = 70°, Nshots = 1, TSL = 50, 42, 34, 26, 18, 10, 2 msec, and number of slices = 7–10.In humans, 2D multislice ECG-gated T1ρ MRI were performed 2 weeks apart in different imaging sessions.Late gadolinium enhanced (LGE) MRI was performed in patients using a 2D multislice, short-axis, phase-sensitive inversion recovery pulse sequence . Approximately 15 minutes prior to LGE MRI, 0.15 mmol/kg gadolinium-based contrast agent  was administered intravenously. In the patient with chronic scar, LGE and T1ρ images were acquired at the same end-systolic cardiac phase and during an end-expiratory breathhold. Even though this strategy reduced the influence of motion, residual myocardial motion was observed in images due to respiration and small variations in sinus rhythm. This issue was more problematic when the subjects were unable to hold their breath or were uncooperative.To mitigate cardiac motion, T1ρ and R2 mapping were implemented into the online reconstruction software utilizing the Image Calculation Environment (ICE) framework of the clinical MRI System . Each T1ρ image series consisted of 8 images. Frame 4 (TSL = 34 msec) was chosen as the reference frame as it showed moderate T1ρ contrast and, in most cases, less motion compared to other frames. Two-frame image registration was performed between each of the 7 moving frames and the reference frame (frame 4).To further reduce the effects of residual motion, we investigated image-based optical flow (OF) motion correction. The OF algorithm ,19 was iTo quantify the accuracy of motion correction, we measured the Dice similarity coefficient (DSC) between image pairs with large, moderate and no motion before and after motion correction. DSC was defined as:1ρ relaxation to assess their accuracy and precision (We tested three models of Trecision . The mai1ρ MRI accuracy was quantified as the percent error N = 3 measurements and σ(Tρ1) the standard deviation. The intra-class correlation coefficient (ICC) was used to assess the T1ρ ROI measurement reproducibility between different scans (R software package). ICC values > 0.75 represent a good agreement . In both previous reports, motion and heart rate correction were not discussed, but could reduce T1ρ reproducibility. As was observed in Previous CMR T studies ,27 were mans. In , relaxatThere was moderate qualitative correspondence between T1ρ and LGE lesions. Specifically, for the patient with ischemic heart disease, T1ρ MRI was consistent with non-transmural scar at a mid-ventricular imaging slice. The reduced wall thickness indicated a very large apical aneurysm and this was supported by LGE hyperenhancement. The spatial distribution of the hyperintense region was consistent with scar, since the lesion appeared predominantly in the mid-myocardium. For HCM patients, there was asymmetric septal wall thickening of the anterosuperior right ventricular insertion zone and this corresponded to elevated T1ρ and LGE lesions. In a fourth patient with non-ischemic cardiomyopathy, there was elevated midwall T1ρ corresponding to a similar LGE lesion pattern. There were several features that were inconsistent, such as the apparent LGE scar size in the ischemic patient or relative lesion position in HCM patients. Myocardial or patient motion may have contributed to incomplete overlap. In this study, LGE scans were performed 10–20 minutes after pre-contrast T1ρ scans and LGE was performed in diastole and T1ρ in systole. Other studies have also reported moderate correspondence between LGE and T1ρ. In van Oorschot et al., double-blinded overlap of LGE and T1ρ in 21 ischemic patients was 72% and unblinded was 74% . Inconsi1ρ MRI using similar parameters [1ρ measurements, it was desirable to change the field-of-view instead of parameters that would affect the number segments and readout duration. The bias for all flip angles and segment sizes was low. The range of T1ρ relaxation times was 10 msec in the normal subject group, but does not account for potential effects of age or gender in these populations and may impact the detectability of diffuse disease.We observed that single-shot bSSFP imaging at high flip angle (70°) had high accuracy compared to the standard, partially because bSSFP has lower perturbation of the transverse relaxation compared to spoiled gradient echo sequences, even at very high flip angles . The accrameters , primari1ρ MRI arising from pulse sequence parameter selection. In particular, Bloch equation simulations showed that proper choice of pulse sequence parameters is essential to reduce bias and reproducibly measure T1ρ relaxation times in the heart. Motion was a major contributing factor to error in cardiovascular T1ρ mapping. Our initial experience using breath-held multi-shot T1ρ imaging was highly unsatisfactory due to the presence of image artifacts, which caused inconsistency in phase encoded k-space data. Single-shot imaging and OF motion correction was found to improve the quality of the T1ρ map  fraction, upstream coronary perfusion or tracer kinetics may alter contrast agent distribution in tissue and LGE signal intensity. T1ρ is sensitive to interactions between tissue water 1H and the macromolecular environment. Increased myocardial fibrosis associated with extracellular matrix expansion may reduce water 1H rotational correlation times and increase T1ρ. In addition, T1ρ imaging has shown increased signal intensity in areas of edema [1ρ MRI. A study by Wang et al. [1ρ maps and LGE cardiac magnetic resonance using quantitative thresholding in HCM patients. In this group, myocardial disarray and replacement fibrosis may contribute to increased T1ρ relaxation.There is considerable interest to characterize myocardial edema and fibrosis in ischemic patients and those with non-ischemic cardiomyopathy. Qualitative visual comparison of the injured myocardium in of edema ,5 and thg et al.  showed s1ρ to T2 mapping, is that T1ρ limits low frequency contributions to the measured relaxation rate, increasing the dynamic range of transverse relaxation times in normal and diseased myocardial tissue. This property was observed in ex vivo myocardial tissue and scar at several B1 amplitudes [1ρ patterns, which may depend on reperfusion time, ischemia-reperfusion injury, extent of coronary ischemia, and hemorrhage. Animal models and prospective studies of T1ρ in humans will be crucial to address these issues.The putative advantage of Tplitudes  and woulplitudes  have non1ρ imaging methods are necessary for parametric mapping of myocardial disease with high accuracy and reproducibility in humans. The methods shown here significantly reduce measurement error of T1ρ relaxation times associated with pulse sequence parameters, magnetic field heterogeneity, and myocardial and respiratory motion and will be essential in the assessment of myocardial disease.In conclusion, highly robust TS1 Dataset(DOCX)Click here for additional data file.S2 Dataset(DOCX)Click here for additional data file.


The prevalence of hypertension has doubled over the previous decade and represents a significant public health problem worldwide. Excess cardiovascular risk due to increased blood pressure shows no evidence of a threshold to at least 115/75 mmHg. Left ventricular (LV) hypertrophy has a strong association with essential hypertension and is an independent risk factor for mortality. However, there is little data on whether systolic blood pressure (SBP) influences LV morphology and function in a healthy population. Furthermore it is not clear if any phenotypical changes are part of an adaptive response to increasing afterload or the beginning of a maladaptive process that ultimately leads to cardiomyopathy.A total of 1258 volunteers  without self-reported cardiac disease underwent high-spatial resolution 3-dimensional cardiac magnetic resonance imaging with computational modeling to characterise LV structure and function. Voxelwise relative wall thickness (RWT), fractional wall thickening (FWT), longitudinal function, and LV shape were the dependent variables. Changes in these parameters associated with SBP were analysed using multivariable linear regression models with adjustment for body surface area, gender, race, age and multiple testing. Results are presented as standardized β coefficients in the anatomic regions where the corrected p-value was <0.05.In our cohort 8.3% of subjects had stage 1 or 2 systolic hypertension (≥140 mmHg), 38.4% had pre-hypertension (120 - 139 mmHg) and 53.3% were normotensive (<120 mmHg). SBP was independently associated with an asymmetric increase in RWT in the three sub-groups  Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London, UK, a British Heart Foundation, UK, project grant (PG/12/27/29489) and special grant (SP/10/10/28431), and a Wellcome Trust-GSK Fellowship Grant.


Venoarterial (VA) and venovenous (VV) extracorporeal membrane oxygenation (ECMO) support is increasingly being used in recent years in the adult population. Owing to the underlying disease precipitating severe respiratory or cardiac failure, echocardiography plays an important role in the management of these patients. Nevertheless, there are currently no guidelines on the use of echocardiography in the setting of ECMO support. This review describes the current state of application of echocardiography for patients supported with both VA and VV ECMO.The online version of this article (doi:10.1186/s13054-015-1042-2) contains supplementary material, which is available to authorized users. The use of extracorporeal membrane oxygenation (ECMO) in adults has grown over recent years, particularly venovenous (VV) ECMO for respiratory failure . A recenThe two main configurations of ECMO currently used are VV ECMO, for respiratory support, and venoarterial (VA) ECMO, for cardiorespiratory support Fig. . VV ECMOPrior to initiating ECMO support, a comprehensive echocardiographic examination should be undertaken, as permitted by the patient’s hemodynamic condition Table . CardiovThe choice between VV and VA ECMO support will depend on the underlying etiology of the patient’s decompensation. Whilst the incidence of RV dysfunction has been dramatically reduced in patients with acute respiratory distress syndrome (ARDS) by the implementation of protective lung ventilation, it still remains as high as 25 % , 15. EveEchocardiographic features of RV dysfunction include RV chamber dilatation, flattening of the interventricular septum, creating a D-shaped LV with an eccentricity index greater than 1; right atrium (RA) and tricuspid valve (TV) annular dilation, with significant tricuspid regurgitation (TR); and RV contribution to the apex of the heart, typically visualized in the transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE) four-chamber view. Objective measurements of RV systolic function include the tricuspid annular plane systolic excursion; the tricuspid annular systolic peak velocity (S’), using tissue Doppler imaging; and fractional area change. McConnell’s sign, severe basal and mid RV hypokinesia with apical hyperkinesia, is indicative of acute onset pulmonary hypertension , 17.The RV systolic pressure can be estimated using the simplified Bernoulli equation, by measuring the peak velocity of the TR jet. Increased pulmonary artery (PA) pressure can also be estimated by pulse wave Doppler interrogation of the PA systolic flow. The presence of a biphasic waveform and a PA acceleration time (time from the onset of systole to time to peak pressure) shorter than 100 ms are indicative of increased pulmonary pressure . These nAlthough imperfect, the objective assessment of the LV includes the measurement of its size along with global and regional function. The presence of thin walls usually indicates a chronic process. Similarly, a dilated left atrium (LA) will be in keeping with chronically elevated left atrial and ventricular diastolic pressures. The global function can be assessed by the modified Simpson’s method, to give an estimate of ejection fraction (EF) . The conPre-extracorporeal life support, a TTE or TEE study is useful to detect certain important pathologies. The initiation of VA ECMO increases the LV afterload and the severity of any pre-existing aortic regurgitation will worsen, leading to increasing LV dilatation, pulmonary edema and risk of subendocardial ischemia secondary to increased myocardial oxygen consumption and wall stress –22. The Similarly, the presence of TV pathologies should be assessed. Although extremely rare in adults, presence of tricuspid stenosis will compromise the flow of the oxygenated blood from the RA to the RV. Acute severe TR with ensuing increased right atrial pressures and right to left shunt might manifest with severe hypoxemia, by opening a patent foramen ovale (PFO). The presence of intracardiac shunts, such as an atrial septal defect or a PFO, may not impact oxygenation directly whilst the patient is supported with ECMO; it may, however, have consequences when weaning from ECMO, as an increase in right heart pressures during the weaning process could precipitate a right-to-left shunt through an atrial septal defect or PFO.Examination of the aorta is essential, as aortic dissection may be the underlying cause of hemodynamic instability and urgent surgical repair may be warranted. Additionally, aortic dissection is a relative contraindication to VA ECMO.The presence and size of any pericardial fluid must be determined to enable differentiation between a pre-existing effusion and an iatrogenic collection due to cannulation.Normal variants and embryological remnants might be found and should be reported, especially the presence of prominent Chiari network or the presence of dilated coronary sinus with or without a persistent left superior vena cava (SVC). A prominent Chiari network might hinder proper advancement of the cannulae and expose the patient to a higher risk of thrombosis. A dilated coronary sinus can potentially be easier to be cannulated: if accidentally cannulated, in the presence of a persistent left SVC, oxygenation can be compromised, with oxygenated blood being reinjected toward the left arm instead of the RA .There are currently no recommendations on which imaging modality is superior to guide ECMO cannulation. Insertion may be guided by fluoroscopy, TTE or TEE. Each of these modalities has its advantages and disadvantages. Echocardiography has the ability to determine the exact position of the cannula, although one should be cognizant of the presence of artifacts that might be misleading. It also allows for prompt diagnosis of any cannulation complications, such as pericardial effusion or aortic dissection.Prior to cannulation, a thorough examination of vascular anatomy will assist in determining any potential barriers to cannulation. It allows identification of thrombus, vessel stenosis, aneurysms or severe atheromatous disease, thus assisting cannulation. The size of the venous drainage cannula is a major determinant of blood flow in the ECMO circuit; therefore, an attempt is made to insert the largest cannula possible. Measuring the diameter of the vessels may aid the choice of cannula size , 25. The2) removal. This may be achieved with two cannulae, typically inserted in the femoral vein, and advanced into the inferior vena cava (IVC), and the internal jugular vein, advanced into the SVC. Alternatively, both femoral veins are cannulated and the reinjection cannula is advanced into the RA. The other option is a single, dual-lumen cannula inserted into the SVC via the right internal jugular vein. Visualization of the guidewire within the correct vessel is paramount to safe cannula insertion.In VV ECMO, the percutaneous approach is typically the method of choice. The blood is drained from the venous system and returned to the patient’s venous system after oxygenation and carbon dioxide  bicaval dual-lumen cannula is designed to drain blood from both the IVC and SVC, and return oxygenated blood into the RA, with the flow directed towards the TV Fig. . Its adv2 removal. In peripheral VA ECMO the venous drainage is similar to VV ECMO, with the drainage cannula positioned at the IVC-RA junction. The return cannula is usually inserted through the femoral artery, with the tip sitting in the iliac artery or distal aorta. Aortic ultrasound can be used to visualize the guidewire within the upper abdominal aorta, to avoid malposition of the arterial cannula within a branch vessel. In central VA ECMO the reinjection cannula is typically inserted directly into the patient’s ascending aorta.As with VV ECMO, in VA ECMO blood is drained from the venous system, but returned into the arterial system after oxygenation and COFew studies in the pediatric literature have reported the added value of echocardiography to guide insertion and correct placement of ECMO , 35. IntIdeally a daily echocardiogram should be performed whilst the patient is on ECMO, since other methods to assess cardiac output may be unreliable Table . Indeed,One important use of serial echocardiograms is to monitor cardiac chamber size to ensure adequate emptying of the ventricles. In addition, aortic valve opening is paramount. In peripheral VA ECMO, the retrograde aortic blood flow competes with the stroke volume ejected from the LV. A closed aortic valve will ultimately lead to LV distention and thrombus formation , should be observed on echocardiography.There are few reports of echocardiographic monitoring of cardiac function during VV ECMO Table  5, 55, , 55, 56.On VV ECMO, recirculation occurs when the tips of the cannulae are located too close together, resulting in further patient hypoxemia. Cannulae may be repositioned as necessary . On VV EAs previously mentioned, limited flows during ECMO support are frequent both on VV and VA ECMO. Although this is usually related to patient positioning or hypovolemia, it is important to exclude the presence of an intra-cannula thrombus (Additional file The use of systemic anticoagulation makes patients on ECMO more susceptible to bleeding and potential pericardial collections. However, even in the presence of a pericardial effusion, the clinical and echocardiographic diagnosis of tamponade remains challenging, especially on VA ECMO, as the modification of RA and RV pressures may preclude appropriate analysis of chamber collapse and of its clinical significance.To our knowledge, there are currently no data on the utility of evaluating RV function by echocardiography during weaning from VV ECMO support. However, acute hypercapnia may precipitate pulmonary hypertension, reopening a PFO and leading to acute RV failure.Most of the data pertaining to weaning derive from VA ECMO, although weaning strategies are highly center dependent and without well-defined standard operating procedures , 63. WeaAttempts have been made to delineate parameters beyond the usual EF and ventricular size, to predict successful weaning from VA ECMO . Whilst in situ (Additional file One of the main concerns after decannulation is the presence of thrombus or obstruction that may have not been identified when the cannulae were Echocardiography plays a crucial role at every step of ECMO support. At the time of consideration, it can confirm the diagnosis and help in defining the choice between VV and VA ECMO. Although, it is unlikely that utilization of echocardiography by itself will directly improve the outcome of patients supported on ECMO, echocardiography may help to reduce complications and guide clinicians in the daily management of these complex patients . It provThere are currently no guidelines with respect to the optimal monitoring of patients on ECMO. Our review has emphasized specific echocardiographic parameters that might be important to follow over the course of ECMO support. Many questions remain unaddressed and require further investigation. For instance, the benefits of echocardiography during insertion of ECMO and during maintenance of VV ECMO support and weaning need to be better defined. Moreover, guidelines for standardized echocardiographic measurements during weaning from VA ECMO would help to guide physicians caring for these patients. Finally, the utility of monitoring RV function during VV ECMO support requires further evaluation.In conclusion, echocardiography is an essential monitoring tool in the care of patients on ECMO. Further investigations and guidelines should help delineate its use for patients on ECMO support.


GATA4, ZFPM2, NR2F2 and WT1, and signaling pathway components, including members of the retinoic acid pathway. Mutations in these genes affect diaphragm development and can have pleiotropic effects on pulmonary and cardiac development. New therapies, including fetal endoscopic tracheal occlusion and prenatal transplacental fetal treatments, aim to normalize lung development and pulmonary vascular tone to prevent and treat lung hypoplasia and pulmonary hypertension, respectively. Studies of the association between particular genetic mutations and clinical outcomes should allow us to better understand the origin of this birth defect and to improve our ability to predict and identify patients most likely to benefit from specialized treatment strategies.Congenital diaphragmatic hernias (CDHs) and structural anomalies of the diaphragm are a common class of congenital birth defects that are associated with significant morbidity and mortality due to associated pulmonary hypoplasia, pulmonary hypertension and heart failure. In ∼30% of CDH patients, genomic analyses have identified a range of genetic defects, including chromosomal anomalies, copy number variants and sequence variants. The affected genes identified in CDH patients include transcription factors, such as  Summary: In this Review, Kardon et al. discuss the complex etiology of congenital diaphragmatic hernia, as revealed by comprehensive genomic analyses and modeling in mice, and highlight the need for new therapies to treat this developmental disorder. Birth defects represent some of the most complex challenges in medicine. A structural problem in one organ can have associated comorbidities in many other systems because defects in one organ, such as the heart or diaphragm, can affect the development or function of another, such as the lungs or because the structural defect is part of a multisystem genetic syndrome . The hetBochdalek hernia: A developmental diaphragmatic defect that involves the lumbocostal triangle at the posterior-lateral chest wall; clinicians often use this term to imprecisely describe many types of CDH.Congenital diaphragmatic hernia (CDH): Diaphragmatic hernias that involve the posterior-lateral diaphragm and present in newborns with respiratory distress.Ductus arteriosus: Fetal anatomical shunt between the pulmonary and systemic circulation. In CDH patients with severe pulmonary hypertension, the ductus arteriosus is often kept open by treatment with a prostaglandin E1 (PGE1) infusion to decrease the workload on the right ventricle.Eventration: Abnormally thin diaphragm usually associated with muscularization defects.Fetal endoscopic tracheal occlusion (FETO): Fetal surgical procedure in which the trachea is occluded  to cause fetal lung fluid accumulation, which induces the stretching and possibly accelerated development of the lungs.Morgagni hernia: A hernia that occurs in the anterior diaphragm just posterior  to the sternum. These hernias are not usually discovered in newborns, and are not usually associated with pulmonary hypoplasia.Pleuroperitoneal folds (PPFs): Transient pyramidal structures at the base of the embryonic thoracic region that give rise to the muscle connective tissue and central tendon of the diaphragm.Pulmonary hypertension: High blood pressure in the vascular system of the lungs. CDH patients often have cardiopulmonary failure that is marked by severe pulmonary hypertension.Pulmonary hypoplasia: Lungs that are small due to abnormal development, as seen in patients with CDH.The diaphragm is a skeletal muscle that normally separates the thoracic and abdominal cavities and is essential for respiration. Defects in diaphragm development are common, occurring in about 1 in 3000 births worldwide , and areRecent advances, including decreased sequencing costs and the ability to make mouse models more easily, have allowed researchers to study CDH more effectively, leading to new insights into the genetic and developmental contributors to CDH, which we review here. We also discuss the cardiopulmonary consequences of CDH, and the available and emerging treatment options.The diaphragm consists of two muscle domains. The costal diaphragm is a domed sheet of muscle composed of a radial array of muscle fibers, which extends from the ribs to a central tendon . The cruSevere CDH that presents at birth is usually associated with co-morbidities in other organs . ApproxiCurrently, the clinical management of CHD largely consists of supportive care with surgical repair of the diaphragm postnatally. This care includes respiratory support with positive ‘gentle’ ventilator pressures, modulation of the pulmonary vascular system, measures to prevent right-heart failure by allowing for patent ductus arteriosus shunting . An impode novo mutations constitute a significant fraction of the genetic alterations predisposing babies to developing CDH. Mutations in particular CDH-associated genes or chromosomal regions are incompletely penetrant for CDH (GATA6) and nuclear receptor subfamily 2 group F , have also been associated with other congenital anomalies, including congenital heart disease and pancreatic agenesis  and single-gene mutations. CDH can be caused by chromosomal anomalies . After uGATA4   , FRAS1-r) FREM1; , fibrill2; STRA6  and FBLN6 , insertions and deletions (indels), or large CNVs are expected to contribute significantly to the etiology of these cases. Studies of trios of unaffected parents with CDH-affected children identified, via cytogenetic and microarray analyses, de novo pathogenic CNVs (affecting one or more genes) in 4% of CDH patients (de novo (as well as inherited) SNVs, indels and CNVs. Using WES on 39 trios of unaffected parents and CDH children, the DHREAMS study (http://www.cdhgenetics.com/dhreams-study.cfm) identified an excess burden of de novo variants that are likely to disrupt or be deleterious to genes highly expressed during diaphragm development  in mice has also implicated mesothelial cells associated with PPFs as a cellular source of CDH  to mark and follow the fate of these structures during development. Most studies have relied on analyses of histologically stained sections whose orientations are not uniform. Future progress will be enhanced by the whole-mount analysis of embryos in which structures that give rise to the diaphragm are labeled with specific antibodies or Cre alleles.The complexities of early diaphragm development pose a major barrier to discovering whether common pathways or processes underlie the development of CDH. While three embryonic structures  play vital roles in diaphragm development, other structures, such as the posthepatic mesenchymal plate (PHMP), could be important . There iLung defectsPremature arrest of airway branchingDecreased number and size of alveoliLong-term obstructive and restrictive lung diseaseAirway hyper-reactivityAbnormal diffusion capacityPulmonary vascular defectsPulmonary hypertensionPremature arrest of arterial branchingDecreased proximal vessel sizeDecreased alveolar capillary densityIncreased vascular smooth muscle thicknessEctopic positioning of vascular smooth muscleDecreased response to vasodilating cuesIncreased circulating vasoconstrictorsCardiac defectsIncreased incidence of congenital heart diseaseDecreased size of left-sided structuresDuctal and intra-cardiac shuntRight heart dysfunction/failureAlthough abnormal diaphragm development is the defining hallmark of CDH, the high rate of mortality and the long-term disability of CDH patients are largely due to abnormal lung and pulmonary vasculature development and function, which cause lung hypoplasia and pulmonary hypertension  Dillon . In CDH Normal lung development depends on the regulation of mechanical forces within the chest and lungs . HoweverGATA4 and ZFPM2 in CDH patients and mice lead to defects in diaphragm development and CDH  and Slit mouse mutants. ROBO and SLIT proteins are best known for their function in axon guidance and angiogenesis  limited the response of these patients to tracheal occlusion. However, reaching such a conclusion is difficult without knowing the baseline mortality rate in patients undergoing this procedure in the absence of pathogenic CNVs  can be life-saving. For example, it is now common practice to maintain an open ductus arteriosus see see . In addiAlthough we have made significant advances in improving the outcomes of CDH patients – through improved prenatal diagnosis and the use of interventions such as FETO and ECMO – the morbidity and mortality of CDH remains high, especially in patients who have other associated anomalies. Advances in genomics, coupled with functional studies in animal models, are increasingly identifying the causes of CDH in both familial and sporadic cases. Through these approaches, we are beginning to elucidate the mechanisms and molecular pathways that are responsible for diaphragm and lung development abnormalities in CDH patients. A key challenge will be to understand which molecular pathways are most commonly disrupted and contribute to diaphragm and lung defects in CDH. An additional challenge will be to understand what causes the phenotypic variability and different clinical outcomes of CDH patients (or their mouse model counterparts) who share the same genetic mutation. We believe that the combined efforts of clinical investigators and developmental biologists will lead to new insights into the etiology of CDH that will improve patient prognosis and care as well as identify future targets for therapy.


Indexed LV mass was mildly increased in HTX patients . LV myocardial deformation indices were all significantly reduced, expressed by global circumferential strain , basal strain , mid-ventricular strain , apical strain , basal rotation , and torsion . EMBx demonstrated ACR grade 0 R in 3 HTX cases, ACR grade 1 R in 11 HTX cases and ACR grade 2 R in 4 HTX cases. When comparing clinically non-significant ACR (grades 0–1 R vs. ACR 2 R), basal rotation, and apical rotation were worse in ACR 2 R patients . Pediatric HTX recipients demonstrate reduced biventricular systolic function and decreased myocardial contractility. Myocardial deformation indices by CMR may serve as non-invasive markers of graft function and, perhaps, rejection in pediatric HTX patients.Acute cellular rejection (ACR) compromises graft function after heart transplantation (HTX). The purpose of this study was to describe systolic myocardial deformation in pediatric HTX and to determine whether it is impaired during ACR. Eighteen combined cardiac magnetic resonance imaging (CMR)/endomyocardial biopsy (EMBx) examinations were performed in 14 HTX patients . Biventricular function and left ventricular (LV) circumferential strain, rotation, and torsion by myocardial tagging CMR were compared to 11 controls as well as between patients with and without clinically significant ACR. HTX patients showed mildly reduced biventricular systolic function when compared to controls [LV ejection fraction (EF): 55 ± 8% vs. 61 ± 3,  Advances in donor and recipient selection, surgical techniques, and medical management have substantially improved survival of children after heart transplantation (HTX) –3. DespiAbnormal left ventricular (LV) torsion and biventricular systolic dysfunction have been reported in pediatric HTX recipients , 7–11, aThis is a single-center, prospective cross-sectional cohort study. The study was approved by the institutional research ethics board and informed consent was obtained from all participants and/or their legal guardians at the time of enrolment. All children and adolescents after HTX who underwent a clinically indicated EMBx between April 2010 and March 2011 were invited to undergo a CMR scan on the same day. EMBx were requested either as part of routine ACR surveillance (17 EMBx) or as follow-up after treatment of ACR (1 EMBx). None of the EMBx were performed because of a suspicion of ACR. CMR examination was conducted immediately before the EMBx in all participants, either in an awake cooperative patient or under the same anaesthesia as the EMBx. Exclusion criteria were general contraindications to undergo CMR, arrhythmia interfering with CMR acquisition as well as poor CMR image quality. Family members of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) who underwent CMR screening for the condition were recruited as controls. Individuals with any signs or symptoms of ARVC, including abnormal CMR findings, were excluded from the control cohort. Patient charts were reviewed for age of the organ donor, ischemia time of the donor heart, bypass time at HTX, and immunosuppressive medications at time of CMR/EMBx. Where available, the reports of fluoroscopic angiography (within 1 year of CMR/EMBx) were reviewed for signs of cardiac allograft vasculopathy (CAV) in accordance with the International Society for Heart and Lung Transplantation (ISHLT) grading system ½), where H is the height in centimeters, and W is the weight in kilograms. LV mass was also indexed for LV EDV, to allow for comparison of LV mass relative to LV size.Biventricular end-diastolic volume (EDV), end-systolic volume (ESV), and EF, as well as LV mass were analyzed in the usual fashion , using cThe analysis of CMR tagging images was performed by a single observer with 10 years of experience in CMR, who was blinded towards the patients’ clinical status, and the results of the endomyocardial biopsies. The images were analyzed using ‘HARP’ software  , 16. TraCardiac catheterization for EMBx was performed using a right internal jugular venous approach. Four to five endocardial samples were taken from the right ventricular (RV) aspect of the interventricular septum. Experienced cardiac pathologists, who were blinded towards the imaging findings and the patients’ clinical status, performed the histological analysis of the specimens. Biopsies were clinically graded according to the 2005 nomenclature of the ISHLT for ACR as 0, 1 R, 2 R, or 3 R  and antiT test was used to express differences between patients and control subjects. Correlation between variables was assessed using Pearson’s correlation coefficient. Statistical significance was indicated by p < 0.05.Analyses were done in both a SPSS software package  and R 3.1.2 . All datFourteen pediatric HTX recipients  and 11 controls  participated in the study. Donor age was 15.1 ± 9.3 years (8 days to 29 years). Ischemic time and bypass time at HTX had been 209 ± 73 min and 121 ± 59 min, respectively. Immune suppression consisted of Tacrolimus and mycophenolate mofetil in 13 HTX patients, supplemented by Sirolimus in one and prednisone in another HTX patient. In addition, 11 HTX patients received statins and 10 HTX patients received antihypertensive medication. Two patients were studied on more than one occasion: one patient underwent two CMR/EMBx investigations (5 months apart) and another patient had 4 combined CMR/EMBx investigations . Coronary angiography was performed in 9 of 14 patients, showing no evidence of CAV .A total of 18 combined CMR/EMBx investigations were analyzed and results are summarized in Table p = 0.02 and p = 0.04, respectively)  (Table p = 0.03)  , while LV mass/EDV correlated with global strain  , and apical strain . Reduced LV torsion correlated with basal strain  and apical rotation . Myocardial deformation and biventricular EFs were not associated with ischemic time and bypass time at HTX in our study.Increased LV mass correlated with apical strain . Late and early time points after HTX did not differ with regards to rotation, torsion, ventricular volumes, LV mass, and ejection fractions. When comparing only patients without significant rejection (ACR 0 or 1 R), mid-ventricular and apical strain were no longer statistically different between early and late after transplant, although a trend prevailed (p = 0.06 for both).When HTX patients were stratified by early  versus late  CMR/EMBx after HTX, strain at mid-ventricular and apical levels were better in the ‘late’ group , but not for biventricular dimensions and ejection fractions, and the other myocardial deformation indices. When comparing only the 14 first CMR studies between patients with non-significant ACR and those with significant ACR, basal and apical rotation remained worse in patients with ACR 2 R .Patients with clinically non-significant ACR (grades 0–1 R) were compared with HTX patients with more significant ACR (grade 2 R), showing that basal rotation and apical rotation were worse in patients with ACR 2R  [Controversy persists over which strain dimension is primarily decreased after HTX and affected the most during ACR. In contrast to our and Miller’s studies which focused on circumferential strain , severaldult HTX , 30, 31.ade 2 R) , 26, 31.Torsion describes the wringing motion of the LV cavity secondary to rotation at the base and at the apex in opposite directions. In comparison with rotation, torsion is a more comprehensive parameter of the LV’s twisting motion as it represents the spiral orientation of LV fibers, incorporating both basal and apical rotation , 10, 11.Donofrio et al. did not relate rotation and torsion to the presence of ACR . In the The principal limitation of this study is—as discussed—the small sample size, particularly the group of HTX patients with grade 2 R ACR, which limits the generalizability of the results. Two patients were studied on more than one occasion which may have influenced the comparison between patients between controls and HTX and between those with significant ACR and those with ACR 0/1 R. However, most of the differences between patients and controls persisted when only one CMR per patient was analyzed. In summary, the observations in this study are hypothesis-generating and must be substantiated in larger studies. Furthermore, while EMBx is the gold standard for the diagnosis of rejection, it may not be reflective of the LV myocardium. This principal shortcoming of EMBx for rejection surveillance may have obscured further associations between CMR markers and rejection.Pediatric HTX recipients have mildly reduced biventricular systolic function and abnormal myocardial deformation indices, expressed by impaired LV circumferential strain, rotation, and torsion. These indices may serve as markers of graft function in pediatric HTX patients. Left ventricular rotation is reduced with increased severity of ACR. Studies in larger populations are necessary to clarify whether CMR metrics of myocardial contractility can be used to screen for ACR.


The aim of the present study was to assess the association of the presence and amount of late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) with cardiovascular adverse events in patients who survived the first year after cardiac transplantation (HTx).©, Berlin, Germany; 0.15 mmol/kg) and using a segmented inversion-recovery gradient echo sequence. The primary endpoint was a composite of first occurrence of major cardiovascular adverse events which required hospitalization (MACE): CV death, congestive heart failure, redo transplant, arrhythmias requiring hospitalization , coronary revascularization, the secondary endpoints were all-cause death and cardiovascular death. Survival of patients was estimated by Kaplan-Meier analysis, for each end point Cox multivariate models were constructed.We enrolled 48 patients  at various stages after HTx (median 9.88 yrs). All patients underwent standard CMR at 1.5 T, images were acquired with retrospective ECG gating and during repeated single breath-holds. Balanced steady-state free precession were used to obtain cine images  in three long-axis planes and in contiguous short-axis slices. LGE images were acquired in matching short-axis and long axis planes starting 10 min after intravenous injection of gadolinium-DTPA  with a median amount of 9.16 g (IQR 3.01 to 21.21) corresponding to 6.4% (IQR 2. 3 to 13.25) of LV mass. Cardiac allograft vasculopathy (CAV) was diagnosed in 54% LGE positive and 23% LGE negative patients (p = 0.057). Primary and secondary end-points were recorded during the follow-up period median 5.16 years (IQR 4.33 to 6.52). Ten patients died and 26 were readmitted because of MACE. LGE presence at CMR was associated with an increased risk of sustaining an index event during follow up shown by the Kaplan-Meier survival curves . Multivariate Cox analysis identified as independent predictors of MACE a diagnosis of CAV , left ventricular end systolic volume index , LGE mass , LGE % of left ventricular mass . Independent predictors of all-cause death were CAV , LGE mass , LGE % of left ventricular mass  whereas cardiovascular death was predicted by CAV  and LGE mass .In survivors after 1 year from HTx the presence of CAV and the amount of LGE are strongly associated with MACE and mortality.