Aortic stenosis (AS) causes left ventricular (LV) pressure overload, leading to adverse LV remodeling and dysfunction. Identifying early subclinical markers of LV dysfunction in patients with significant AS is critical as this could provide support for earlier intervention, which may result in improved long-term outcomes. We therefore examined the impact of severe AS and its consequent increase in LV afterload on myocardial deformation and rotational mechanics by 2-dimensional (2D) and 3-dimensional (3D) speckle-tracking echocardiography.We prospectively measured various strain parameters in 168 patients  with severe AS and LV ejection fraction (EF) ≥50%, and compared them to normal values found in literature. 2D and 3D images were analyzed for global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), basal rotation, apical rotation, and peak systolic twist. We further assessed the degree of concordance between 2D and 3D strain, and examined their association with measures of LV preload and afterload.P = 0.003 for 3D twist, P < 0.001 for all others). Agreement between 2D- and 3D-GLS by concordance correlation coefficient was 0.49 . GLS was correlated with valvulo-arterial impedance, a measure of LV afterload .Patients with severe AS exhibited significantly lower GLS and GRS but higher GCS, apical rotation, and twist by 2D and 3D echocardiography compared with published normal values (Patients with severe AS demonstrated lower-than-normal GLS and GRS but appear to compensate with higher-than-normal GCS, apical rotation, and twist in order to maintain a preserved LVEF. GLS showed a modest correlation with valvulo-arterial impedance. Aortic stenosis (AS) is the most common native valve disease and is characterized by left ventricular (LV) pressure overload. In patients with AS, the LV faces two afterloads: one from the valvular obstruction itself and the other from reduced systemic arterial compliance , 2. ProgGlobal longitudinal strain (GLS) by 2-dimensional (2D) speckle-tracking echocardiography can be used to detect early LV systolic dysfunction and has been proposed as a more sensitive way to detect a decline in LV function in patients with AS –11. HoweThe objectives of this prospective study were to: 1) to determine how myocardial deformation is affected in patients with severe AS and preserved LVEF compared with normal values found in literature; 2) to compare 2D to 3D echocardiographic measures of LV myocardial deformation in patients with severe AS; and 3) to characterize the relationship between LV preload and afterload and myocardial deformation.2, and who had a preserved LVEF, defined as ≥50%, on transthoracic echocardiography. The study was performed at Mayo Clinic, Rochester, Minnesota from November 1, 2014 to August 31, 2015. Patients were excluded if they were < 18 years of age; if they had an irregular rhythm; if they had moderate or greater aortic or mitral regurgitation; or if image quality was inadequate. The final analysis included 168 patients. This study was approved by the Mayo Clinic Institutional Review Board, and all patients gave informed consent to participate.We prospectively recruited 181 patients with severe AS, defined as a mean gradient > 40 mmHg or an aortic valve area < 1.0 cmEach patient underwent a standard 2D and a real-time 3D transthoracic echocardiogram in the left lateral decubitus position, using commercially available equipment  with a fully sampled matrix-array transducer (X5–1). Vital signs were measured in all patients immediately before the echocardiographic examination. Studies were performed by an experienced cardiologist (X.B.). 3D full-volume images were acquired from the apical window with a 6-beat acquisition, a high volume rate , and full coverage of the entire LV by the pyramidal volume. Patients were instructed to hold their breath during image acquisition. Images were optimized for endocardial border visualization by adjustment of overall gain, compression, and time gain compensation before acquisitions. The acquired 2D images and 3D full-volume images were analyzed offline with TomTec 4D Echo software, version 4.6 .For 2D echocardiography, the standard 2D, M-mode, and Doppler measurements were obtained in accordance with guidelines from the American Society of Echocardiography . LV end-For 3D echocardiography, three standard apical views were automatically extracted from the 3D full-volume data sets. The mitral annulus and the LV apex were manually selected as the landmarks to initialize the LV boundaries. Then, the 3D endocardial surface was automatically reconstructed at end-diastole and end-systole. The endocardial surface reconstruction was manually adjusted, as necessary, and the papillary muscles were included as part of the LV cavity. Subsequently, 3D speckle-tracking was automatically characterized. The software provided longitudinal, radial, circumferential, and principal tangential strain time curves for the 16 segments and peak global strain, as well as averaged peak strain at three LV levels  , which can be calculated by the formula: Zva = (SAP + MGnet)/SVI, where SAP is the systolic arterial pressure, MGnet is the mean net pressure gradient transvalvular pressure, and SVI is the stroke volume index. Therefore, Zva represents the valvular and arterial factors that oppose ventricular systole by absorbing the mechanical energy developed by the left ventricle /cardiac output; systemic vascular resistance index (SVRI) was measured by the formula: SVRI = [80 × ]/cardiac index . Briand entricle .For reproducibility of 2D- and 3D-speckle-tracking echocardiographic measurements of deformation parameters, 20 patients were randomly selected and reanalyzed by the same observer to determine the intra-observer agreement and by a second experienced echocardiographer, who was blinded to the initial results, to determine the inter-observer agreement. Both measurements were obtained with the intra-class correlation coefficient (ICC).t-test using reference values obtained from two large meta-analyses [t-test. Data were analyzed with JMP 10.0 software  and MedCalc statistical software, version 11.4.1.0 . A P value < 0.05 was considered statistically significant.Data were presented as mean ± standard deviation (SD) for continuous variables and as number (percentages) for categorical variables. The various strain parameters measured in this study were compared to those of normal healthy patients previously published in literature including two meta-analyses with pooled data from > 2000 patients each for both the 2D and 3D global strain measurements –25. Agreanalyses , 24. AllTable 2 while the calculated indices of LV afterload were as follows: total arterial stiffness, 0.8 ± 0.3 mmHg/mL; total arterial compliance, 1.5 ± 0.7 mL/mm Hg; systemic vascular resistance, 1368 ± 438 mL/mm Hg/m2; systemic vascular resistance index, 2628 ± 788 dynes•s/cm− 5; and Zva, 3.7 ± 0.7 mmHg/mL/m2.Echocardiographic characteristics of cohort patients with severe AS and preserved LVEF are listed in Table P<0.0001 for all) and higher apical rotation and peak systolic twist  compared with those of healthy subjects previously published in literature. There was no significant difference in 2D and 3D basal rotation in patients with severe AS compared with normal values.The parameters of 2D and 3D speckle-tracking strain for both groups are shown in Table ρ = 0.54, P < 0.0001) for patients with severe AS. The agreement between 2D and 3D images was poor for GCS , and GRS , and peak systolic twist . An excellent level of agreement existed between 2D and 3D LVEDV  . The other deformation parameters, including apical rotation and peak systolic twist in 2D and 3D showed no correlation with Zva. Among all of the indexes of afterload, only Zva demonstrated the modest correlation with 2D and 3D GLS. Among the parameters of preload, indexed LVEDV demonstrated a weak correlation with 2D and 3D GLS .GLS by 2D and 3D was correlated with ZTable Our study provides the most comprehensive simultaneous 2D and 3D characterization of myocardial mechanics to date in patients with severe AS and preserved LVEF. These patients demonstrated subclinical LV systolic dysfunction in the form of reduced GLS and GRS along with concomitant increases in GCS, apical rotation, and peak systolic twist, which may represent compensatory mechanisms to maintain the LVEF within normal limits. We were able to demonstrate these changes in mechanics by both 2D and 3D speckle-tracking echocardiography. Furthermore, GLS showed a weak correlation with indexed LVEDV, a measure of preload, and a modest correlation with valvulo-arterial impedance, a measure of afterload.Characterization of myocardial mechanics through the echocardiographic assessment of myocardial deformation, or strain, can provide a more thorough representation of LV contractile function . ThroughPatients with severe AS and preserved LVEF in our cohort exhibited lower-than-normal GLS, a finding consistent with that found in several prior studies –19. In pReduced GLS was accompanied by increased GCS in our cohort of patients with severe AS and preserved LVEF, in keeping with the tendency for circumferential strain to increase in order to maintain a normal LVEF . HoweverIn addition to increases in circumferential strain, apical rotation and peak systolic twist were also significantly higher than normal in our cohort of patients with severe AS and preserved LVEF, which is consistent with prior findings , 29, 31.Few prior studies have assessed changes in radial strain and basal rotation in patients with severe AS , 7, 11. va is a simple index that provides an estimate of the afterload imposed on the LV and is an important index of AS severity and predictor of LV dysfunction and outcomes [va is moderately elevated in patients with severe AS, and aortic valve replacement often only reduces the valvular component of afterload and has no effect on the arterial compliance of elderly patients, which may be due to other comorbidities, such as hypertension and atherosclerosis [va but no significant relationship between Zva and other deformation parameters. GLS also correlated with increasing LVEDV and E/e’ ratio. The increase in LVEDV and Zva represents a hemodynamic load that markedly increases wall stress and results in depressed myocardial contractility [In patients with degenerative AS, arterial compliance is frequently reduced, which contributes to increased afterload and decreased LV function. Hence, the LV is often subjected to a double afterload from valvular obstruction and from reduced systemic arterial compliance , 2. Zva outcomes , 36–38. clerosis . Our stuactility .va.Previous studies have reported conflicting results of comparisons of 2D and 3D speckle-tracking echocardiography measurements, possibly because of major differences in the study populations such as sample size and the severity of AS, as well as methodology such as software used for measurement of strain , 40–43. Theoretically, 3D imaging should be more accurate as it can overcome well-known limitations of 2D imaging by avoiding foreshortened apical views, providing a more complete picture of myocardial deformation in three dimensions, and reducing out-of-plane motion, which may affect the accuracy of LV strain and twist measurements. However, the lower temporal and spatial resolutions of 3D images are potential limitations that could adversely affect the accuracy of 3D measurements acquired at the lower frame rates , 43. NevOur study had several limitations worth considering. First, it was a single-center observational study, which may reduce the generalizability of the results. However, the prospective design of the study allowed for more precise patient selection and more comprehensive data collection that would not have been possible with a retrospective design. Second, given the elderly cohort of patients with severe AS, we were unable to recruit similar healthy age- and sex-matched subjects for comparison. Nevertheless, we used, to our knowledge, the best available reference values that have been previously published in literature for comparison including two large meta-analyses of 2D and 3D global strain. Third, our patients had pertinent comorbidities such as coronary artery disease, which could theoretically influence myocardial deformation. However, it would not be possible to fully account for all comorbidities that could affect strain in these patients. Our cohort therefore reflects a real world population of patients with severe AS with comorbid conditions. Fourth, we did not validate the deformation measurements against reference standards such as tagged magnetic resonance imaging or sonomicrometry. Furthermore, the relatively low frame rate of real-time 3D echocardiographic imaging could potentially lead to underestimating strain values. As well, the relatively high body mass index in our cohort may have led to poor image quality. Nevertheless, the similar findings obtained on both 2D and 3D provided a degree of quality assurance. Finally, it may not be possible to extrapolate our exact measurements to other ultrasound machine systems or 3D speckle tracking software, although we suspect that the pattern of deformation abnormalities observed may still be consistent.In patients with severe AS, GLS and GRS are reduced while GCS, basal rotation, and twist are increased, presumably to maintain normal cardiac output and LVEF. These findings were shown by both 2D and 3D speckle-tracking echocardiography. Reductions in GLS were shown to correlate with measures of increased preload and afterload. Our study provided the most comprehensive 2D and 3D characterization of myocardial deformation to date in patients with severe AS and preserved LVEF.


An increased risk of ischemic stroke has been reported in patients with Parkinson's disease (PD). Atrial fibrillation (AF) is strongly associated with ischemic stroke. Prolonged atrial electromechanical delay (EMD) is an independent predictor for the development of AF.  The aim of the present study was to evaluate the atrial conduction parameters in patients with PD and to assess their relation with the severity of PD.  We prospectively enrolled 51 consecutive patients with newly diagnosed PD and 31 age- and sex-matched non-PD subjects.  To assess atrial electromechanical coupling (PA), the time intervals from the onset of p wave on ECG to the late diastolic wave at the septal (PAs) and lateral (PAl) mitral annulus and lateral tricuspid annulus (PAt) were measured on Tissue Doppler Echocardiography (TDE). The difference between PAs-PAl, PAs-PAt, and PAl-PAt were defined as left intra-atrial, right intra-atrial, and interatrial EMD, respectively. P-wave dispersion (PWD) was calculated from the 12-lead ECG. p < 0.001). Interatrial, right, and left intra-atrial EMD were also significantly longer in PD patients . There were significant positive correlations between disease severity (UPDRS score) and PWD , left intra-atrial , and interatrial EMD . By multivariate analysis, PWD , LA volume index , left intra-atrial , and interatrial EMD  were found as independent predictors of PD.  PWD, PAs, PAl, and PAt durations were significantly prolonged in the PD group (all  Atrial conduction times were longer and correlated with the severity of disease in PD patients. Prolonged inter- and intra-atrial-EMD intervals were also found as independent correlates of PD. These findings may suggest an increased predisposition to atrial fibrillation in PD. Parkinson's disease (PD) has been associated with an increased risk of ischemic stroke and stroke-related mortality –3. A recProlonged atrial conduction times have been related to both onset and recurrence of atrial fibrillation , 8. TissFifty-one consecutive patients with newly diagnosed PD and 31 age- and sex-matched non-PD subjects were prospectively enrolled between January 1st, 2015 and December 31, 2015. Patients with PD were diagnosed according to the UK Parkinson's Disease Society Brain Bank Criteria . The sevAll patients were evaluated by transthoracic M mode, two dimensional, pulsed wave, continuous wave, colour flow, and TDE using the GE Vivid 3 system  with a 2.5–3.5 MHz transducer. Continuous single lead ECG was obtained from each participant during echocardiography.LV diameter and wall thickness were measured by M-mode echocardiography. LV ejection fraction was calculated by Simpson's method according to the American Society of Echocardiography guidelines . The mita > 5% difference between the measurements of two cardiologists were not included.TDE was performed by adjusting the pulsed Doppler signal filters to acquire the Nyquist limit of 15–20 cm/s and using the minimal optimal gain. Motions were recorded simultaneously with electrocardiogram in lead II to assess the relation between atrial electrical phases and myocardial motion. To assess atrial electromechanical coupling (PA), the time intervals from the onset of p wave on ECG to the late diastolic wave at the septal (PAs), and lateral (PAl) mitral annulus and lateral tricuspid annulus (PAt) were measured on TDE. The difference between PAs-PAl, PAs-PAt, and PAl-PAt were defined as left intra-atrial, right intra-atrial and interatrial EMD, respectively , 9. Echop value < 0.05 was considered statistically significant. Categorical variables were expressed as frequencies (percentages). Continuous variables were presented as mean ± standard deviation . Categorical variables were compared using the chi-square or Fischer's exact tests. Group means for continuous variables were compared using independent sample t-test. Pearson's correlation test was performed to assess the correlation between atrial conduction times and the severity of PD. Multivariate regression analysis was used to identify independent predictors of PD. Age, gender, hypertension, diabetes, LA volume index, PWD, and EMD intervals were included in the multivariate models.Statistical analysis was performed using SPSS 16.0 . A two-tailed Fifty-one consecutive PD patients (mean age: 66.3 ± 12.4 years and 71% men) and 31 non-PD subjects (mean age: 69.8 ± 12.7 years and 52% men) entered the study. Mean UPDRS score of the PD group was 35.3 ± 17.9 . Baseline demographic and clinical characteristics of the PD and non-PD groups are provided in p=0.006). Mitral E/A was lower and mitral E-wave deceleration time was higher in the PD group, but both failed to reach statistical significance . The remaining standard echocardiographic parameters were comparable between the two groups.Echocardiographic parameters are provided in p < 0.001). Left intra-atrial, right intra-atrial, and interatrial EMD were significantly longer in PD patients . PWD showed significant correlations with left intra-atrial  and interatrial EMD .Atrial conduction time intervals are shown in r=0.36, p=0.008), left intra-atrial , and interatrial EMD  (p=0.017), LA volume index , left intra-atrial , and interatrial EMD  were found to be independent predictors of PD (There were significant positive correlations between disease severity (UPDRS score) and PWD (p=0.002) . By multrs of PD .The major findings of the present study are (1) patients with newly diagnosed PD are more likely to have abnormal atrial conduction times as assessed by prolonged PWD, PAs, PAl, PAt, intra-atrial, and interatrial EMD; (2) prolonged atrial conduction times were significantly correlated with the severity of PD as assessed by the UPDRS score, and (3) PWD, left intra-atrial, and interatrial EMD were found to be independent predictors of PD.Atrial fibrillation is the most common sustained arrhythmia in clinical practice . ElectroPrevious clinical studies have shown electrocardiographic PWD to be a predictor of paroxysmal atrial fibrillation . PWD refPatients with atrial fibrillation have an increased risk of stroke even after adjustment for risk factors . PD has Several potential explanations may be postulated for the pathophysiologic mechanisms by which atrial fibrillation and PD may be related. First, both atrial fibrillation and PD are associated with an increased inflammatory state –23. NeurA limitation of our study might be that the study population was not followed up in terms of development of atrial fibrillation. Another limitation might be that data regarding inflammatory and oxidative markers were not studied. Also because of the limited number of patients included in the study, our findings require validation and further studies with larger patient groups with follow-up for arrhythmias are needed.In conclusion, the present study showed that atrial conduction times were prolonged in patients with newly diagnosed PD. Furthermore, atrial conduction parameters were significantly correlated with the severity of PD. Our findings might contribute to risk stratification of PD patients with regard to atrial fibrillation.


The correct differentiation of an irregular, narrow-complex tachycardia has crucial implications for the therapeutic management of these conditions. In this article we present a differential diagnostic and treatment approach to irregular, narrow-complex tachycardias. A 54-year-old lady with longstanding hypertension and a recent diagnosis of atrial fibrillation presented to the emergency unit with a two-day history of palpitations and mild dizziness. This was preceded by a few weeks of pedal oedema, with progressively worsening dyspnoea and effort intolerance. Clinically, she was mildly distressed with peripheral oedema, a respiratory rate of 24 breaths a minute and blood pressure of 129/84 mmHg. She had a low-volume pulse that was irregularly irregular, with a rate of around 120 beats per minute. The jugular venous pressure was not elevated, but her apex beat was diffuse and minimally displaced. On auscultation she had heart sounds of variable intensity, but no murmurs. Her chest had soft crackles in the bases.Echocardiography revealed a non-dilated left ventricle with signs of concentric left ventricular hypertrophy (LVH) and impaired left ventricular (LV) function [LV ejection fraction (LVEF) of 40%]. The left atrium was dilated and there was mild mitral regurgitation (MR). She had normal pulmonary artery pressures and right ventricular (RV) function.Her ECG  showed aThe patient’s heart failure therapy was optimised with diuretics. She was initially treated with a rate-control strategy and oral anticoagulation in accordance with standard international guidelines.The differential diagnosis of an irregular, narrow-complex tachycardia includes atrial fibrillation, atrial flutter with variable atrio-ventricular (AV) block and multifocal atrial tachycardia. Atrial fibrillation (AF) is the most common cause of an irregular, narrow-complex tachycardia, affecting approximately 33 million people worldwide.8In atrial fibrillation there is chaotic, asynchronous atrial impulse propagation, with multiple wavelets that course irregularly through the atria and reach the AV node at irregular intervals, which cause irregular AV nodal conduction. On the ECG , atrial 9Atrial flutter (AFL), the second most common pathological supraventricular tachyarrhythmia, shares many risk factors with atrial fibrillation.In contrast to AF, flutter waves are regular and discrete, uniform in morphology (in keeping with the organised re-entry circuit) with a fixed atrial rate usually around 300 per minute (can range between 240 and 360). The ventricular rate depends on the degree of AV block . In patients with AV node disease or who take drugs that slow AV conduction, the ventricular response to atrial flutter may be irregular, though less erratic than in atrial fibrillation.10Multifocal atrial tachycardia (MAT) is a rare condition that occurs in patients with advanced pulmonary disease or who are receiving theophylline treatment.10The correct distinction between AF, AFL and MAT is of paramount importance, since the three conditions require different therapeutic approaches.To reduce the risk of thromboembolism, appropriate oral anticoagulation should be offered to patients with AF and AFL and who do not have any contra-indications to vitamin K antagonists (VKAs) or non-vitamin K oral anticoagulants (NOACs).Uncontrolled tachyarrhythmia due to atrial fibrillation or flutter can result in acute cardiac decompensation as well as tachycardia-induced cardiomyopathy (TIC) in the long term.13In atrial fibrillation, rhythm control was not found to be superior to rate control in the AFFIRM and RACE trials.16In atrial flutter, a rhythm-control strategy is often preferred over a rate-control strategy. Radiofrequency ablation is a highly effective treatment of typical atrial flutter involving the right atrial cavotricuspid isthmus. For these reasons, rate control of atrial flutter is usually not a long-term option, especially if patients are symptomatic, if the ventricular rate is difficult to control (which is not uncommon) and if there is an associated tachycardia-induced cardiomyopathy.19MAT is treated by treating the underlying lung disease.


T2* and apparent diffusion coefficient (ADC) measurements in a sub 10‐minute scan time.A combined diffusion‐relaxometry MR acquisition and analysis pipeline for in vivo human placenta, which allows for exploration of coupling between T2*‐ADC spectra using an inverse Laplace transform.We present a novel acquisition combining a diffusion prepared spin echo with subsequent gradient echoes. The placentas of 17 pregnant women were scanned in vivo, including both healthy controls and participants with various pregnancy complications. We estimate the joint T2*‐ADC spectra demonstrate clear quantitative separation between normal and dysfunctional placentas.T2*‐diffusivity MRI is promising for assessing fetal and maternal health during pregnancy. The T2*‐ADC spectrum potentially provides additional information on tissue microstructure, compared to measuring these two contrasts separately. The presented method is immediately applicable to the study of other organs.Combined  It is implicated in many major pregnancy complications, such as pre‐eclampsia (PE) and fetal growth restriction (FGR).T2* relaxometry—which has the potential to estimate oxygenation levels,Placental MRI is emerging as a technique with substantial promise to overcome some disadvantages of ultrasound. For example, ultrasound parameters of fetal wellbeing are imperfect for determining which fetuses have late‐onset FGR and are at greatest risk of adverse perinatal outcome, as opposed to those that are constitutionally small but healthy.T2* relaxometry exploits the inherent sensitivity of the transverse relaxation time to the biochemical environment of tissue. In particular, the paramagnetic properties of hemoglobin mean that the T2* time constant can be used as a proxy estimation of oxygenation.T2* is generally lower in FGR cases.T2* constant of the tissue. No diffusion weighting is typically applied to these scans. Applying diffusion gradients with different strengths  and directions provides sensitivity to various microstructural length scales and orientations. These measurements are usually taken at a fixed TE. In the placenta, dMRI has shown promise for discrimination between normal pregnancies and FGR,T2* and dMRI studies in the literature, no method has shown sufficient discrimination between healthy pregnancies and those with complications to be introduced into routine clinical practice. Methods which combine multiple distinct measurements may provide a way to overcome this. Supporting Information Table T2* and dMRI studies in the placenta to date.T2* and dMRI‐derived measures are both influenced by the presence and composition of distinct tissue compartments (or microenvironments). Diffusion‐relaxometry MRI can simultaneously measure multiple MR contrasts; for example, by varying both TE and b‐value it is possible to probe the multidimensional T2‐diffusivity (or T2*‐diffusivity) space. MR experiments dating back to the 1990s have simultaneously measured diffusivity and T2T2‐diffusivity,T2‐diffusivityT2‐diffusivity in the placenta,T2*‐ADC spectrum within a clinically viable timeframe. We apply this novel method in the placenta, an organ where T2* and ADC have both been shown to be informative. As well as demonstrating simultaneous estimation of T2* and diffusivity parameters within a clinically viable time, we hypothesize that the joint T2*‐ADC spectrum will provide additional information compared to the individual measures.A major disadvantage of previous diffusion‐relaxometry experiments are the very long scan times required when varying multiple contrast mechanisms, such as the TE and diffusion encoding. In this paper, we propose a combined acquisition and analysis technique which can estimate the 22.1T2* and ADC, as opposed to standard independent multi‐echo gradient echo and diffusion sequences  model.T2* relaxometry and diffusion are p(T2*) and p(ADC) are the T2* relaxation and diffusivity spectra to be estimated from the data. We can solve for these spectra using an inverse Laplace transformation, although this is an ill‐posed problem requiring regularization to smooth the resulting spectra.TE and b are simultaneously varied, the signal is , which can be estimated by a regularized 2D inverse Laplace transform. This contains more information than the individual 1D spectra, and is hence more likely to resolve multiple distinct tissue compartments. Although we emphasize that, due to choice of kernels in the continuum models, these distinct compartments—that is, separate peaks in 2D spectra—are assumed to be the result of monoexponential signal decays.A significant limitation of the models presented in Equations –3) is t is t3) il is e.g. (4)S and informed written consent was obtained prior to imaging. Seventeen pregnant women, with gestational age ranging from 23+5 to 35+4 (weeks + days), were successfully scanned using the described technique. Three of these participants, one of whom also had FGR, were diagnosed with pre‐eclampsia according to standard definitions.4/LO/1169T2*‐diffusivity scan was acquired with the proposed sequence, a dMRI prepared spin echo followed by multiple gradient echos. The number and timing of the gradient echos varied across scans . The fitting consisted of two‐step (grid search followed by gradient descent) maximum log‐likelihood estimation assuming Rician noise, similar to that previously described,T2* was constrained between 0.001 seconds and 1 second, the ADC between 10-5 and 1 mm2 s-1, and S0 between 0.001 and 105. We fixed the SNR for fitting to 20 for all voxels in all scans.We first manually defined a region of interest (ROI) containing the whole placenta and adjacent uterine wall section on the first Equation  voxelwisT2*‐ADC spectrum for each participant from the signal averaged over the ROIs, using the MERA toolbox,T2*‐ADC spectra voxelwise in all participants. We next quantified the spatial variation in T2*‐ADC spectral components across the placenta and uterine wall with volume fraction maps, using a similar approach to Benjamini et alT2*‐ADC domain into regions. These boundaries were the same across all participants, and are given in Table T2*‐ADC spectrum, we then calculated the weight of the voxelwise spectra contained in each of these regions. By normalizing these weights to sum to 1 across all regions, we produced spectral volume fraction estimates for each voxel. Figure We calculated the 3T2* model fits . We observe three peaks, clearly separated by ADC value but with similar T2* values. ADC and T2* maps show distinctive spatial patterns. The ADC is much higher in the uterine wall than the placenta. T2* maps show distinct “lobes” surrounded by a patchwork of low T2* values, with many lobes displaying a small region of higher T2* in the center. The bottom row of Figure T2*‐ADC space, as described in Methods. The domain with the lowest ADC (e.g. peak 1) is associated with areas within the placenta, and the two domains (peaks 2 and 3) with higher ADC are more prominent in the uterine wall.The first panel in Figure T2* maps across all participants from the combined T2*‐ADC fit. The patterns are consistent with those previously reported in the literature.T2* encircled by low T2* borders are clearly visible, and most likely correspond to placental lobules, with high T2* indicating the presence of oxygenated blood. In agreement with previous observations, the regions with low T2* are more prominent in pre‐eclampsia,Figure ADC maps Figure  also shoT2*‐ADC spectra for ROIs containing the placenta and uterine wall. We clearly observe separate peaks in all control participants, strongly suggesting the presence of multiple tissue compartments with distinct properties. In the vast majority (11/12) of these spectra from healthy controls, we see at least three clearly separated peaks. The ADC values of two of these peaks are typically above the diffusivity of water in free media  than by T2* value. We also observed three distinct peaks in placentas from chronic hypertensive women. Interestingly, we did not see three distinct peaks in any spectra from participants with pregnancy complications . There is a distinct pattern in the T2*‐ADC spectra for the three PE participants—a left and downward shift in the lowest peak. This suggests a decrease in both ADC and T2* distributions compared to control placentas. There is a similar leftward shift in the PE+FGR placental spectrum; however, the downward shift is not as pronounced, with the middle peak appearing to merge with the lowest peak. The peak with the highest ADC often appears to span the boundary of the domain in which the inverse Laplace transform is calculated. This is likely because we are unable to sample enough low b‐values to accurately estimate this very fast diffusing component—i.e. there is signal in the b = 0 volume, which has all attenuated by the b = 5 s mm-2 volume.Figure Spectral volume fraction maps showed similar patterns across all control participants  acquisition space. This in turn allows visualization of the 4.210-1 mm2 s-1. Additionally, in nearly every control participant (11/12) we observe two further clearly distinct peaks, with ADC around 2×10-3 mm2 s-1 for the lower, and between 10-2 and 10-1 mm2 s-1 for the middle peak  comparable to the diffusivity of water in tissue, is associated with water which is not subject to significant incoherent flow effects—this may be within tissue or slow‐moving maternal blood. The highest ADC compartment is associated with perfusing fetal blood, and the intermediate compartment with fluid transitioning between the maternal and fetal circulations—a significant proportion of which may reside within tissue. This is consistent with the spectral volume fraction maps for the peaks with higher ADC  of the middle and higher peaks2.T2*The lowest peak has a lower 3.The lowest peak has a lower diffusivityWe observed three main trends in the T2* mirrors the previously reported decrease in T2* in pre‐eclampsia placentas.T2* values have also been observed in FGR placentas.T2*‐ADC spectrum in a single plot, showing clear separation between the control and pregnancy complication  participants. We plot the position of the spectral peak with the lowest ADC in the T2*‐ADC domain, with the marker area corresponding to the peak’s volume fraction. In this way, we capture both the peak shift, and the higher volume fraction due to the disappearance of the middle or higher peaks. Although these results are highly encouraging, we clearly need to scan many more participants, both control and women with pregnancy complications, to determine the discriminative power of these measures.In placentas from women with pre‐eclampsia, we generally saw all three trends Figure . The low4.3.1T2*‐ADC spectrum. There are a number of known weaknesses for this method, including the need for regularization. In this study, we chose minimum amplitude energy regularization. Future work could assess the utility of alternative optimization approaches, such as spatially constrained,We used an “out‐of‐the‐box” inverse Laplace transform toolbox to calculate the T2* estimates are generally lower than those previously reported.T2*, such as spiral artery inlets. It could also be due to signal attenuation due to diffusion during the gradient echoes, something which we did not account for in our analysis.Our T2*‐ADC spectral analysis assesses the data in two dimensions, but there are more dimensions to the data—such as diffusion gradient direction —which we did not include in our analysis. Therefore, this data set has the potential to be further analyzed, for example, with microstructural models that account for anisotropy in the signal.The presented b‐values and gradient directions optimized for dMRI at a single TE,T2* relaxometry and dMRI acquisition parameters is 1D . However, when moving to combined T2*‐diffusion this becomes a 2D problem—for example, in the isotropic case we need to choose optimal TE‐diffusion encoding pairs. In future, we plan to optimize these TE‐diffusion encoding values in order to give the best sampling of the 2D parameter space, and enhance estimation of the 2D spectra.In this study, we used 4.4T2* and diffusivity in less than 10 minutes. These two MR contrasts have been shown elsewhere to be sensitive to placental pathologies, we hypothesize that their simultaneous assessment could enable better separation of healthy and poorly functioning placentas. This is supported by the fact that we did not see consistent correlation between T2* and ADC values FIGURE S3 Spectral volume fraction maps, obtained by summing the T2*‐ADC spectrum weight within the domain where ADC<25×10-3 mm2 s-1FIGURE S4 As Figure S3, but for the domain where 25×10-3 mm2 s-1<ADC<200×10-3 mm2 s-1FIGURE S5 As Figure S3, but for the domain where 200×10-3 mm2 s-1<ADC<1000×10-3 mm2 s-1FIGURE S6 Correlation between T2* and ADC from combined ADC‐T2* fit within placental ROIs. Horizontal blue dashed lines represents the approximate diffusivity of water in free media at 37∘C (3×10-3 mm2 s-1)Click here for additional data file.


MPP) are important clinical adjuncts in cardiac resynchronization therapy (CRT) pacing aimed at reducing the rate of non‐response to therapy. Mixed results have been achieved using MPP and it is critical to identify which patients require this approach and how to configure their MPP stimulation, in order to achieve optimal electrical resynchronization.Quadripolar lead technology and multi‐point pacing (ECGi), using the CARDIOINSIGHT™ inverse ECG mapping system, could identify alterations in electrical resynchronization during different methods of device optimization. In no patient did a single form of programming optimization provide the best electrical response. The effects of utilizing MPP were idiosyncratic and highly patient specific. ECGi activation maps were clearly able to discern changes in bulk LV activation during differing MPP programming. In two of the five subjects, MPP resulted in more rapid activation of the left ventricle compared to standard CRT; however, in the remaining three patients, the use of MPP did not appear to acutely improve electrical resynchronization. Crucially, this cohort showed evidence of extensive LV scarring which was well visualized using both CMR and ECGi voltage mapping.We sought to investigate whether electrocardiographic imaging (ECGi in the optimization of non‐responders to CRT, as it allows the fusion of activation maps and scar analysis above and beyond interrogation of the 12 lead ECG.Our work suggests a potential role for  Initially devices were programmed according to the default manufacturer settings. The following day after implantation, each patient underwent an iterative CRT optimization procedure, guided by non‐invasive body surface mapping, looking to identify the optimal pacing settings.Patients on optimal medical therapy (OMT) meeting European Society of Cardiology (ESC)2.1Global Right/Left Ventricular Electrical Synchrony (VVsync): the mean activation time in the right ventricle minus the mean activation time in the left ventricle. Previously described as ventricular electrical uncoupling.Global Biventricular Total Activation Time (VVtat): a measurement of the total time required for both ventricles to activate. Previously described as VVTAT.Global Left Ventricular Total Activation Time (LVtat): a measurement of the total time required for all portions of the left ventricle to activate. Previously described as LVTAT.Global Left Ventricular Dispersion of Activation (LVdisp): a measure of the dispersion of the activation times in the left ventricular region of interest.A non‐invasive electrophysiological mapping study was performed using a high resolution electrocardiographic mapping system , as previously described.Given the primary objective of CRT is to restore regional activation synchrony, we defined the optimal activation pattern as that which achieved the most effective degree biventricular resynchronization whilst simultaneously minimizing both biventricular and LV activation times. Electrical synchrony is specifically assessed by VVsync, where a figure of 0 represents identical LV and RV activation time.Epicardial voltage maps were also collected, in order to identify any areas of low voltage which may indicate areas of myocardial scar and fibrosis. Where possible, these were correlated against CMR data, see Figure 2.2The patient's baseline presenting rhythm––either intrinsic sinus rhythm or RV paced rhythm––was first analyzed using directional activation maps.The VV offset was optimized according to the maximal improvement in aortic pulsed‐wave Doppler velocity time integral, as previously described.™  was used to identify the RV‐paced to LV‐sensed timings for each of the poles on the quadripolar lead. MPP was then programmed to pace the pole with the longest delay first and the pole with the shortest delay second. The right ventricular lead was always paced last. We delivered MPP with 5, 10, and 20 ms delays between each stimulus using both a local bipole configuration‐distal (D1) to mid 2 (M2) and proximal (P4), and an extended bipole configuration‐ D1 to RV coil and P4 to RV coil. This resulted in our testing 6 MPP settings per patient; 3 local and 3 extended bipole. In order to test the different MPP vectors for capture threshold and phrenic nerve stimulation, a number of standard biventricular recordings were also performed which served as comparators for individual patients.Once the optimal AV and VV intervals had been established and programmed, differing MPP settings were then acutely programmed. During each configuration, a non‐invasive electro‐anatomical mapping was obtained. The SJM CRT toolkit33.1A total of five patients were enrolled in the study.3.2The effect of changing AV delays, VV delays, the LV pacing vector, and finally the addition of MPP are shown in Table Epicardial voltage mapping showed the presence of scar in all of the ischemic patients which corresponded to LGE on MRI in the 3 cases where MRI was performed, see Figure 3.3Echocardiography demonstrated severe biventricular impairment and CMR demonstrated delayed sub‐endocardial late gadolinium enhancement consistent with prior infarction of the apex, antero/infero‐septum, and inferolateral wall. The epicardial voltage map was consistent with extensive scarring in the same distribution as the LGE visualized during CMR.3.3.1Intrinsic conduction exhibited the activation pattern typically observed in LBBB; ventricular activation is initiated at the distal branching of the right bundle, with activation of the left ventricular endocardium occurring after a significant delay, as a result of slow conduction through the interventricular septum  Extended Bipolar and Local Bipolar MPP resulted in more rapid activation of the left ventricle compared to optimized echo optimized CRT. It is possible accelerating LV activation has the potential to improve the degree of cardiac resynchronization and as such, may explain the greater hemodynamic improvements™ ECGi system represents a non‐invasive technique capable of assessing the acute response to MPP and may be of use in identifying patients likely to gain the most from MPP as well as how best to configure this multi‐polar pacing.The remaining 3 patients showed evidence of extensive LV scarring which was well visualized using both CMR & ECGi voltage mapping. The use of MPP in this cohort did not appear to acutely improve electrical resynchronization. In part, this may be explained by the focal nature of the scar burden,5This is a small study and the results are hypothesis generating rather than conclusive. Our primary objective was to analyze how myocardial activation varied during device programming optimization and whether non‐invasive body surface mapping technology might be capable of identifying these changes in activation. Our hypothesis did not extend to evaluating rates of response to CRT and given the small number of patients, it would be impossible to draw reliable conclusions. Instead, non‐invasive electrical measurements were analyzed acutely and it is unclear whether these results can be extrapolated to the chronic delivery of CRT. Biventricular pacing which improves the degree of biventricular electrical resynchronization has been associated greater response.6Iterative echo guided AV & VV optimization & quadripolar lead technology in conjunction with MPP are important clinical adjuncts to CRT pacing. The range of programming options provide greater cost efficiency by reducing the need for reintervention after implantation for technical issues including high capture thresholds, lead displacement, and phrenic nerve stimulation.Amongst carefully selected patients; however, the use of optimal device programming can achieve a superior degree of electrical resynchronization when compared to conventional CRT with nominal settings. However, these strategies are not without cost. Echo guided device optimization can be expensive and time consumingOur analysis suggests that judicious use of device reprogramming optimization may be a useful strategy; however, the main issue remains identifying which patients may require this approach and then successfully optimizing their programming to achieve optimal electrical resynchronization. ECGi is a non‐invasive technique capable of accurately delineating the electrical effects of CRT pacing as well as the presence and distribution of myocardial scar. Our work suggests a potential a role for this tool in the optimization of non‐responders to CRT, as it allows the fusion of activation maps and scar analysis above and beyond interrogation of the 12 lead ECG.Authors declare no conflict of interests for this article.


The regimen of the recombinant tissue plasminogen activator (rt-PA) is identical in every case where it is indicated in the treatment of cerebral infarction. We report a case of efficient recanalization of large arterial occlusion after rapid injection of rt-PA.A 78-year-old man was admitted with right-sided hemiplegia and global aphasia that occurred an hour ago.His brain computed tomography (CT) revealed no hemorrhage, suggesting cerebral infarction.Ten percent of a total rt-PA dose was injected over 1 minute promptly. The remainder of rt-PA was designed to be infused for 60 minutes. Unexpectedly, during the study of CT angiography, administration of rt-PA was completed within 5 minutes. CT angiography showed occlusion from carotid bifurcation to the middle cerebral artery.After 2 hours of rt-PA administration, the patient began to regain strength in his right arm and leg. By the next day, he had only mild dysarthria and aphasia. Follow-up CT angiography revealed recanalized internal cervical artery and severe residual stenosis with a plaque. He was discharged without any neurologic symptoms.The infusion protocol of rt-PA administration is established in 1995 and has not changed. Successful recanalization of long segmental large vessel occlusion with only intravenous rt-PA is relatively low. In our case, a high concentration of rt-PA may have influenced the successful dissemination of large thrombus in the whole internal cervical artery. Our case is of significance as it raises the question of unanswered efficacy of diverse injection protocol according to thrombus size and bleeding risk. However, it is known that the rate of recanalization is low when the rt-PA is infused by this administration method, especially in occlusion of a large vessel such as an internal carotid artery (ICA). We report our experience of efficient recanalization of large arterial occlusion without hemorrhagic complication after rapid injection of rt-PA over 7 minutes.Currently, recombinant tissue plasminogen activator (rt-PA) remains the only approved thrombolytic medication in acute ischemic stroke.2A 78-year-old man was admitted to our emergency department with right-sided hemiplegia and global aphasia that occurred an hour ago. His National Institutes of Health Stroke Scale (NIHSS) score of 21. Computed tomography (CT) of the brain performed 20 minutes after arrival revealed no hemorrhage or hypodense lesion. Ten percent of a total rt-PA dose was injected over 1 minute promptly after CT check. The remainder of rt-PA was designed to be infused for 60 minutes. Unexpectedly, during the study of CT angiography, administration of rt-PA was completed within 5 minutes with a significant disparity of the standard rt-PA protocol. Initial CT angiography showed nonvisualization of the ICA from carotid bifurcation to the middle cerebral artery (Fig. Informed consent was obtained from the patient for publication and accompanying images.3,3,4 However, the dosing regimen used in this study was identical to the previous pilot study and did not consider the various administration methods. Although the study demonstrated the long-term clinical benefit of rt-PA compared to placebo, data related to early neurological improvement, which was the primary endpoint, did not reach statistical difference. Additional studies were conducted to extend the therapeutic time window or expand the eligible indication of rt-PA with identical protocol.,5In this case, the rt-PA was administered in a different protocol than the conventional method, resulting in the effective dissolution of the large thrombus without hemorrhagic complication. The conventional infusion protocol of rt-PA administration is established based upon NINDS trial in 1995 and has not changed in both clinical and research field. Further effort to achieve early recanalization and an excellent clinical outcome is crucial in thrombolytic therapy.There may be some limitations in applying the one identical thrombolytic protocol to all acute cerebral infarction. First, considering the short half-life of rt-PA, the primary purpose of intravenous thrombolysis is early recanalization. However, most previous studies have not shown that rt-PA administration is beneficial for early recanalization of large vessel occlusion compared to placebo. Successful revascularization was the most critical factor affecting clinical improvement after ischemic stroke in the previous study. Because the ICA occlusion is more resistant to intravenous rt-PA than the MCA, only 4% of ICA occlusion is completely recanalized.,8 The recanalization rate of whole ICA thrombus will be even lower than simple intracranial ICA. The presence of abundant blood clot in the whole ICA might prevent the delivery of an adequate dose of rt-PA to the thrombus. Nevertheless, the current protocol does not differentiate rt-PA administration between cerebral infarction due to small vessel disease and large artery occlusion. In our case, the high concentration of t-PA may have influenced the successful dissemination of large thrombus in the whole ICA.Second, the rate of successful recanalization depends on the amount of thrombus. Long segmental thrombus located in a large vessel would be less likely dissolved compared to a small thrombus. In previous studies and clinical field, recanalization of large vessels has been observed up to 30% after only rt-PA administration.,10 In a patient with large infarct core, low-dose rt-PA may be administered to reduce the risk of bleeding. The Enhanced Control of Hypertension and Thrombolysis Stroke Study was showed fewer symptomatic intracerebral hemorrhages with low-dose alteplase compared to full-dose. The longer the duration of thrombolytics administration from the onset of symptoms, the higher the risk of bleeding. In the ECASS III trial, intravenous rt-PA administration between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcome despite increased intracranial hemorrhage.In consideration of the administration of thrombolytic agents, another vital aspect is the risk of intracranial hemorrhage. In acute ischemic stroke, the size of cerebral infarction and the time from symptom onset are the main factors related to the risk of intracerebral hemorrhage.Conversely, patients with short time to onset of symptoms may have small infarct core and a lower risk of hemorrhage. In this case, increasing the dose or the administration rate as needed may not increase the bleeding risk to the effect. Despite these findings, there has been no study on the diversity of infusion protocol according to the risk of bleeding, and the guidelines only mention one method of administration.Currently, endovascular thrombectomy is the most effective and essential treatment for a patient with large vessel occlusion. However, mechanical endovascular procedures require the facilities, equipment, and professional staff. Therefore, intravenous thrombolytic therapy is still an important treatment in many situations. Further studies are needed to increase the recanalization rate and early neurological recovery through intravenous rt-PA treatment. It is essential to make patient-tailored treatment decisions, such as recent studies of an endovascular thrombectomy or wake-up stroke that show effective results with different patient selections.This case is not an intended study, and there is a limit to generalization. However, our case is of significance as it raises the question of unanswered efficacy of various injection protocol according to thrombus size and bleeding risk and further discussion and well-designed studies are warranted.Conceptualization: Jaechun Hwang.Investigation: Jaechun Hwang.Validation: Jin-Sung Park.Writing – original draft: Jin-Sung Park.Writing – review & editing: Jaechun Hwang.


Ventricular assist device (VAD) is usually attached by an inflow cannula to the apex of the systemic left ventricle (LV), but very few cases with implantation of the VAD in the morphologic right ventricle (RV) have been described.We describe the case of a 41-year-old male who developed severe systemic RV failure related to a Mustard procedure he had as an infant for treatment of TGA. His heart failure was refractory and irreversible, and therefore, he underwent VAD implantation for systemic RV support. Although the patient developed pulmonary congestion on postoperative day (POD) 5, he was discharged on POD 60. He is now looking forward to receiving heart transplantation.Placement of a VAD for systemic RV failure could be a life-saving treatment in adult patients with heart failure due to congenital heart disease. After an atrial switch operation (Mustard or Senning operation) for correction of transposition of the great arteries (TGA) or in patients with congenitally corrected TGA (CCTGA), discordant atrioventricular and ventriculoarterial connections are both present. Owing to this double discordance, a reconnection of the heart vessels is necessary to allow for proper blood circulation. This can be done with the Mustard or Senning procedure, which will help prevent cyanosis. Patients who undergo such arterial switch procedures are surviving to adulthood, but they often develop RV heart failure a few decades later. Implantation of ventricular assist device (VAD) is a useful therapy for patients with end-stage heart failure as a bridge to heart transplantation. However, adult congenital heart disease (ACHD) patients with TGA post-Mustard procedure or CCTGA have unique anatomical and physiological characteristics that can make clinical management or surgical procedures more challenging.The patient was a 41-year-old man  with dextro-TGA who underwent balloon atrioseptostomy treatment at birth because of desaturation. He also had a Mustard procedure  at 10 months of age and required surgical repair for pulmonary vein stenosis at 2 years of age. At 41 years of age, he developed severe systemic RV failure and pulmonary edema  and carperitide (24 ng/kg/min), a recombinant atrial natriuretic peptide with vasodilating and diuretic activity Table . Echocar2, systemic arterial pressure via a right radial artery catheter, bispectral index , and regional cerebral oxygen saturation at the right and left forehead  was initiated before anesthesia induction. After administration of 100% oxygen, general anesthesia was induced slowly by intravenous administration of 3 mg of midazolam, 0.5 mg of fentanyl, and 50 mg of rocuronium. Additionally, dobutamine (3.3 μg/kg/min), nicorandil (1.1 μg/kg/min), which has the dual properties of a nitrate and a potassium channel opener, and carperitide (33 ng/kg/min) were continuously administered to minimize anesthetic-induced cardiac depression. During anesthesia induction and tracheal intubation, his circulatory and respiratory status remained stable. After tracheal intubation, a transesophageal echocardiography probe was inserted. Then, a central venous catheter and right heart catheter were inserted via the right internal jugular vein. The latter catheter (Swan Ganz catheter) was guided to the right pulmonary artery under fluoroscopic control because of his unique anatomy with interatrial baffle.In the operating room, a continuous monitoring of electrocardiography, SpOHis anesthesia depth was controlled at a BIS of 40–60 by a continuous infusion of propofol (3–5 mg/kg/h), remifentanil (0.2–0.3 μg/kg/min), and rocuronium (7 μg/kg/min).A standard median sternotomy was performed. Because his heart was heavily adherent, the cardiac surgeons had difficulty in adhesiolysis. The systemic aorta and systemic atrium were cannulated, and cardiopulmonary bypass (CPB) was instituted. At first, the patient’s aortic valve was replaced with a bioprosthetic valve for moderate aortic valve regurgitation. Subsequently, the trabeculae carneae of the RV, which could disturb the flow to the inflow cannula, were resected via the RV apex; the inflow cannula was positioned at the apex of the RV. The outflow cannula graft was anastomosed to the ascending aorta, and then a Jarvik 2000 VAD  was implanted.At the weaning of the CPB, infusion of dobutamine (3.3 μg/kg/min) and inhalation of nitric oxide (20 ppm), to decrease afterload of the pulmonary LV, was started. The CPB weaning was not difficult, and the VAD was successfully commenced at a pump speed of 10,000 rpm (3–5 L/min). The aortic cross-clamping, CPB, surgery, and anesthesia lasted 200, 296, 628, and 807 min, respectively. Estimated blood loss and urine output were 2051 and 2390 mL, respectively. Overall, 900 mL of crystalloid, 900 mL of colloid, 960 mL of packed red blood cells, 560 mL of fresh frozen plasma, and 200 mL of platelet concentrate were administered. After completion of operation, the patient was transferred to the intensive care unit with ventilator support under propofol sedation.On postoperative day (POD) 2, the patient was weaned from mechanical ventilation. On POD 5, after our surgeons decreased the VAD dial from 3 to 2, the patient developed pulmonary congestion with respiratory distress, decreased arterial oxygen saturation, and elevated pulmonary artery pressure (PAP)  are now surviving into adulthood because of improved surgical repair techniques and management ; howeverSenning performed the first atrial switch procedure for TGA in 1958 , and MusImplantation of VAD in a patient with ACHD, such as after an atrial switch operation for TGA, could be a particularly challenging procedure. A small number of cases describe the implantation of VAD for a morphologic RV –12. BecaThe patient developed pulmonary congestion with increased PAP at POD 5. We presume that the preserved pulmonary LV function and decreased VAD output could easily induce over-filling of the systemic RV in patients after an atrial switch operation. In a previous report, Toyama et al. suggest that it is essential to adjust the systemic VAD flow according to the pulmonary ventricular function and the systemic ventricular filling in case of VAD implantation to a patient with CCTGA .In fact, this case had congestive heart failure following the decrease in VAD dial by the surgeons from 3 to 2 on POD5. Our surgeons decreased the VAD dial in order to open aortic valve because they feared thrombosis at the aortic root. We thought that this procedure could induce pulmonary congestion. Actually, after the intensivists returned the VAD dial from 2 to 3, he recovered from congestive heart failure in combination with NPPV adaptation and the intensified diuretic therapy.Although he underwent surgical repair for stenosis of his pulmonary veins at 2 years of age, there was the potential for residual pulmonary vein obstruction (PVO). In this case, PVO could be one of the major risk factors for pulmonary congestion. However, we unfortunately did not examine for details in this case, and so we could not deny or affirm the existence of PVO. In the perioperative management of VAD implantation for ACHD patients, we must assess the presence or absence of PVO preoperatively. PVO is a congenital or acquired cardiac malformation that is hard to diagnose clinically and could be properly diagnosed by echocardiography, and cardiac catheterization could reveal the site of stenosis morphologically. Additionally, because the volume of the atrium was limited after atrial baffle repair, excessive transfusion could easily induce pulmonary congestion.. During anticoagulant therapy, we must pay attention to systemic bleeding complications.Postoperative anticoagulant therapy of patients undergoing VAD implantation is one of the most important issues. Anticoagulation protocols change by each institution, implanted device, and individual patient. In many cases, to prevent clot formation, both warfarin and antiplatelet drugs, such as aspirin or dipyridamole, are administered for anticoagulation . During VAD placement for systemic RV failure is a life-saving treatment in ACHD patients who encounter end-stage heart failure. Although these patients have unique anatomical and physiological characteristics that can make clinical management more challenging, systemic VAD implantations with systemic RV dysfunction have the potential to improve physiological conditions and can offer a bridge to heart transplantation.


While the number of patients supported with temporary cardiac assist is growing, the existing devices are limited by a multitude of complications, mostly related to contact with the blood. The CorInnova epicardial compressive heart assist device was tested in six sheep using an acute heart failure model. High esmolol dose, targeting a 50% reduction in CO from healthy baseline, resulted in a failure state with mean CO 1.9 L/min. Heart assist with the device during failure state resulted in an average absolute increase in CO of 1.0 L/min, along with a decline in ventricular work to 67.5% of the total LV SW. Combined with repeated success of minimally invasive device implant, the resulting increases in cardiac hemodynamics achieved while still unloading the heart demonstrate the potential of the CorInnova device for temporary heart assist.The online version of this article (10.1007/s12265-018-9854-5) contains supplementary material, which is available to authorized users. An estimated 6.5 million people in the USA alone have heart failure (HF) in some form, with an estimated 26 million people worldwide. This US population is projected to increase to 8 million by 2030, as the incidence is increasing due to aging of the population and increased survival of heart attacks . A growiThe CorInnova device is a cardiac assist device in preclinical development that applies compression to the outside of the heart (epicardium) in synchrony with systole. The primary advantage of the CorInnova device is the non-blood contacting mode of heart assist. All current temporary MCS devices—including intra-aortic balloon pump (IABP), extracorporeal membrane oxygenation (ECMO), CentriMag, TandemHeart, and Impella—have the potential to cause vascular injury, bleeding, and neurologic injury complications . AdditioAs discussed by Moreno et al., a direct cardiac compression (DCC) device that is strategically designed to correct aberrant heart motions and enhance heart contractility may provide both heart assist and a potential means to enable heart recovery—provided that proper deformation of myocardium is needed for heart tissue growth and remodeling , 4. The The CorInnova device is situated within the pericardium and surrounds both ventricles. The device encloses most of the LV free wall and a majority of the RV free wall from the apex to the atrioventricular (AV) groove. Ventricular coverage is limited by the insertion point of the inferior vena cava (IVC) into the right atrium, and therefore resides apical to the AV groove. The device consists of two concentric sets of thin film polyurethane bladders—an inner  fluid-filled buffering component that accommodates any gaps in the interface between the device and heart; an outer bladder component is cycled to inflate with air in synchrony with the native heartbeat, providing active epicardial compression during systole consistent with physiologic cardiac motion. A superelastic Nitinol frame gives the device structure, while enabling minimally invasive self-deployment and diastolic recoil. See Fig. The device was operated using a custom programmable pneumatic drive system—referred to as the Driver. The ovine ECG was acquired using epicardial electrodes and was gated on the R-wave by a custom-gain cardiac trigger monitor . Using a programmable controller, the R-wave gated ECG signal is used to trigger the activation of solenoid valves, which pressurize the active bladders during systole, and vacuum during diastole. A Millar Mikro-Tip® Catheter Pressure Transducer  was used to measure the fluid pressure in the passive chambers, providing a metric of epicardial assist pressure. The device was activated for short periods of time (< 5 min) during this study with intermittent periods of device standby to observe the relative acute effects of device assist.Six (6) separate acute ovine, non-GLP studies were conducted for this investigation, with two excluded from data analysis due to suboptimal device fit around the heart. All experiments were conducted under an animal use protocol (AUP) that was approved by the Texas A&M University Institutional Animal Care and Use Committee (IACUC) or the Texas Heart Institute IACUC. Each study utilized a single, anesthetized adult domestic cross ovine (50–78 kg). Upon induction of anesthesia, catheters were placed to facilitate the administration of medications as well as for monitoring of vital parameters. Central venous pressure (CVP), aortic pressure (AoP), and left ventricular pressure (LVP) were monitored by either fluid-filled catheters or a Millar Mikro-Tip® Catheter Dual Pressure Transducer (SPR-751) placed across the aortic valve. A left thoracotomy was performed to access the base of the heart, where a small incision was made in the pericardium to expose the aortic root for placement of a Transonic COnfidence Flowprobe® around the ascending aorta to measure cardiac output (CO) before closing.An apical approach to the heart was achieved through a substernal incision with removal of a portion of the xyphoid process. After performing the xyphoidectomy, the surgeon opened a small (approximately 1 in. diameter) incision at the pericardial apex, and then constructed a pericardial cradle to stabilize the pericardial edges. A pericardiogram was performed for imaging of the epicardial structures by infusing contrast media directly into the pericardial sac through the apical incision . Prior tA high dose of esmolol was utilized to create an acute model of a heart with significantly depressed function. In addition to creating a stable, dose-dependent failure, esmolol has the benefit of rapid metabolism with a clearance half-life of only 9 min—allowing for rapid return to the baseline state . After an = 31 ± 3 cardiac cycles per 20-s sample). The samples of cardiac cycles were averaged over the 20-s selection using LabChart, and then averaged in Microsoft Excel to provide an overall effect for each animal as well as a comprehensive trend. A two-tailed, paired t test was used for comparison between device standby and assist for each parameter, with an alpha level of 0.05 (Excel).ADInstruments PowerLab data acquisition hardware and LabChart software were used to continuously record all physiologic parameters and CorInnova device data. Paired samples of 20 s of device standby and successive device assist were collected for analysis of acute effects; the duration was selected in order to average out pressure artefact due to anesthesia respirations by including two full respiration cycles in the sample  was subtracted off the total LV SW to quantify the percentage of the total LV SW due to endogenous ventricular work (WLV); overall, while the LV SW during device standby was 100% due to the work done by the heart (WLV), during device assist, the average WLV was responsible for only 67.5% of the total LV SW, with WD responsible for the remaining 32.5% of LV SW. This metric of LV unloading is plotted in Fig. Overall, the CO increased by 1.0 ± 0.2 L/min and the LV stroke work (LV SW) increased by 968 ± 132 mmHg*mL (+ 102%). Moreover, the work due to the device during assist  improved by 16 ± 3 mmHg, and similarly, the peak LVP improved by 16 ± 4 mmHg with assist. Venous return pressures showed minimal change; the overall CVP decreased by 1 ± 1 mmHg, and the LV end-diastolic pressure (LV EDP) decreased by 1 ± 2 mmHg).This study demonstrated the acute effects of the CorInnova heart assist device in an ovine model of acute heart failure, building on the pilot investigation of the device described in detail previously by Moreno et al. The repeated success of minimally invasive deployment on the first attempt shows significant confidence in the practical implantation and implementation of this device in the clinical setting. Moreover, the device was implanted at two different study locations with different surgical teams, further demonstrating the ease of use of this technology. While a subxyphoid incision is the best surgical approach to access the apex of the heart in the ovine anatomy, a mini-left thoracotomy would be more appropriate for an apical approach for implantation of this device in humans. It is anticipated by author WEC, a cardiothoracic surgeon who performed the animal implant, that the total skin-to-assist time would be less than 10 min in an acute clinical setting. Given that many patients with heart failure are considered high risk for major surgery, a minimally invasive device placement procedure is advantageous; moreover, the procedure avoids a median sternotomy, which may be later required when bridging to implant a long-term ventricular assist device (VAD). The swift deployment time—as quick as 15 s after access to the pericardial sac is established—opens up opportunities for other applications of this technology, such as in cases of acute cardiogenic shock.Short-term assist for BTD is a justified strategy for stabilizing a patient prior to implantation of a long-term VAD; with more stable hemodynamics and improved end-organ function, the patient has reduced risk of poor outcomes. Most importantly, if the patient can be bridged to recovery, they can avoid the unnecessary risk of major surgery, VAD complications, and the cost of an expensive VAD. All existing temporary support devices are associated with several complications, including bleeding, high risk of vascular injury, infection, and/or neurologic complications; patients who have peripheral vascular disease and contraindications to anticoagulation are not eligible for currently approved MCS device support. In contrast, the CorInnova device has the advantage of non-blood contacting biventricular (BiV) support—particularly beneficial when there is risk of thrombosis and/or right-heart failure. In summary, we anticipate that the device may be effective for a multitude of acute heart assist situations, including but not limited to cardiogenic shock, acute decompensated heart failure, myocarditis, post-cardiotomy assist, failure to wean, and for bridge-to-decision in patients with chronic heart failure.The results of the present study demonstrated improved cardiac output and hemodynamic pressures achieved with a relatively low epicardial assist pressure. Furthermore, the work performed by the heart was reduced with device assist. Although systolic changes were consistent, the effect of device assist on the diastolic blood pressure was variable between animals and will need to be further investigated. Additionally, it is unlikely that uniform BiV epicardial compression over-assisted the right heart, where lower pressures are the norm; there was a slight decline in LV EDP with assist, showing no indication of increased LV preload due to elevated pulmonary pressures. It should be noted that only a small reduction in filling pressures was anticipated with assist in the esmolol model due to the low preload associated with this particular failure model; it is anticipated that in future studies with higher preload models of HF, this metric of cardiac unloading will have a more pronounced change with device assist in addition to the reduction in ventricular work. Overall, the decline in ventricular work combined with the slightly reduced CVP and LV diastolic pressures shows evidence that device assist unloads the heart while increasing CO. Another metric for assessing unloading is afterload, and conventionally, SBP is a good measure of afterload because the epicardial pressure is nearly zero. However, when the epicardial pressure is increased with the device assist herein, the myocardial load is reduced because the heart muscle does work against the transmural pressure difference (which is approximated as SBP minus systolic assist pressure).The hemodynamic effects induced by the CorInnova device were on the order of several existing temporary MCS devices. The intra-aortic balloon pump (IABP) has been clinically available for several decades; however, the resulting effects on CO are modest with debatable effect on patient outcomes. A clinical study comparing the hemodynamic effects of the IABP to the Impella 2.5 reported an increase of only + 0.21 L/min from 3.46 to 3.67 L/min in the IABP group . A more Also of note from the Seyfarth study was the figure showing the decline in cardiac power index (CPI) due to the contribution of the heart during the first 14 h post-implant, demonstrating cardiac unloading. This CPI due to the heart was calculated by separating the Impella pump flow from the total CO, and subtracting the contribution of the device from the total CPI. They also showed that endogenous cardiac work of Impella patients was significantly lower than in patients with IABP at all time points . A similECMO can assist in gas exchange with some improvement in CO. However, ECMO increases the afterload on the heart. Additionally, a recent study comparing the outcomes of patients who were bridged with various temporary MCS devices found that veno-arterial ECMO (VA-ECMO) was associated with worse outcomes in LVAD patients than patients who were not bridged to LVAD . This stOther temporary MCS devices, such as the TandemHeart and CentriMag, report higher CO than the CorInnova device. However, the tradeoff is increased invasiveness and risk to the patient. The CentriMag pump is surgically implanted, cannulated left atria (LA) to aorta for LV support or right atria (RA) to pulmonary artery (PA) for right ventricular (RV) support; the CentriMag can also be used peripherally in an ECMO circuit. However, while the CentriMag pump itself can achieve up to 10 L/min flow, it is only approved for up to 6 h for LV support, and RV support up to 30 days under Humanitarian Use only. Similarly, the TandemHeart has the ability to pump up to 4 L/min, with bypass from the LA accessed by a venous transseptal inflow cannula, and outflow to the femoral artery. This allows for oxygenated blood to be pumped from the LA to the systemic circulation via a femoral artery catheter. While these devices have been shown to significantly reduce preload and augment CO, there is high risk of thromboembolism and thus patients receive a systemic heparin regimen for anticoagulation . Given tHeart assist devices similar in concept to the CorInnova device have been explored in the past . More reThe less invasive surgical implantation of the CorInnova device combined with the intrinsic pneumatic attachment method is ideal for bridging the patient to potential device removal upon improvement in myocardial function. More specifically, the device does not require any suturing or cardiac chamber cannulation that ultimately results in myocardial damage—limiting chances of myocardial recovery. In the present acute studies, no bleeding or ecchymosis was observed when removing the device from the heart. However, while the CorInnova device is designed to minimize adhesions, it remains to be seen how easily the device can be removed at the conclusion of chronic studies. Although no universal criteria for MCS weaning to test for removal readiness currently exists, the non-obligatory nature of the CorInnova device permits the magnitude of device assist to be reduced and even halted completely without the risk of thrombogenic complications. In a recent review by Selzman et al., the authors encouraged a paradigm shift towards intentional bridging to device removal—a strategy the CorInnova device is ideal to help achieve .The esmolol acute failure model, although commonly used for preclinical testing of similar devices, has limitations. A high dose of a beta-blocker, such as esmolol, is very effective in reducing the cardiac contractile strength and stroke volume. Additionally, the esmolol model is consistent with other DCC acute heart failure investigations (permitting direct comparison of study results), is low cost, has low risk of animal mortality, and fewer arrhythmias. However, esmolol causes dilation of the great vessels, resulting in significantly reduced pulse pressures and low preload. Therefore, the device needed to overcome significantly reduced preload, which may have affected the recovery of cardiac output; a low preload may have limited the CO effects of epicardial ventricular assist, and yet, a low afterload may have enhanced it. The low preload also limits the observable cardiac unloading effect of the device in regards to reducing filling pressures and will need to be studied in a higher preload HF preclinical model. Additionally, it remains to be seen how a heart with more fibrosed myocardium will react to epicardial compression; it is possible that a stiffer myocardium will respond differently to compressive assist; however, it is still anticipated that the heart will perform less work and overall hemodynamics will improve. Finally, the esmolol model lacks arrhythmias that may be present in certain HF etiologies; the CorInnova device triggers with the native ECG, similar to IABP; however, triggering is gated on the R-wave alone with no consideration of P wave. Thus, it is expected that triggering in patients with, for example, atrial fibrillation can be potentially manageable. Specifically, the RR interval is irregular with atrial fibrillation such that RR can be so short that systole is too brief for device activation. Given that the device is non-obligatory in nature, it is expected that a pause in active assist during these periods of rhythm disturbance conditions will permit device use in most patients. Nevertheless, it could be a limitation and will need to be studied more in the future. While a sample size with four animals showed statistically significant changes in CO, LVSV, SBP, MAP, LVP, and LVSW between device standby and assist, more samples from future studies may show statistically significant changes in HR, DBP, CVP, and LVEDP with device activation.A device-related limitation of significance was the restricted size range of prototypes, and thus, it was possible that the available device(s) for any one study may not have been the ideal size for that particular heart. Preliminary imaging was not completed prior to each study for device sizing; rather, a device was chosen from a set of up to three sizes, based on intraoperative fluoroscopic imaging and by recommendation of the lead surgeon. While the passive component of the device has significant volume and can be adjusted for variations in circumferential dimension, substantially larger hearts were more difficult to accommodate. This was apparent in the animals excluded from data analysis, where the heart was unexpectedly large; these animals experienced acute depression of cardiac function upon deployment. However, additional sizes of the device prototype were available during successive animal studies. Future studies will incorporate a wider range of available device sizes.Results of the current study show the potential of the CorInnova device to assist the failing heart acutely. Minimally invasive surgical implantation was a repeated success, combined with significant recovery of cardiac hemodynamics with device assist during a depressed state. Furthermore, the CorInnova device unloads the heart during assist by reducing the amount of ventricular work. The next phase in developing this technology will include longer-term implantation, an investigation of diastolic effects of assist, and a pilot investigation of the CorInnova device in a chronic heart failure model with dilated growth and remodeling.ESM 1


Failed extubation from mechanical ventilation in critically ill patients is multifactorial, complex and not well understood. We aimed to identify whether combined transthoracic echocardiography, lung and diaphragmatic ultrasound can predict extubation failure in critically ill patients.2O and positive end expiratory pressure 5 cmH2O). Prior to extubation, data collected included ultrasound assessment of left ventricular ejection fraction, left atrial area, early diastolic trans-mitral flow velocity wave (E), early diastolic trans-mitral flow velocity wave/late diastolic trans-mitral flow velocity wave (E/A), early diastolic trans-mitral flow velocity wave/early diastolic mitral annulus velocity (E/E′), interatrial septal motion, lung loss of aeration score and diaphragm movement. At the end of the weaning trial, the rapid shallow breathing index and serum B-type natriuretic peptide concentration were measured. Success and failure of weaning was assessed by defined criteria. Decision to extubate was at the discretion of the treating intensivist. Failure of extubation was defined as re-intubation, non-invasive ventilation or death within 48 h after extubation. Of 53 extubated participants, 11 failed extubation. Failed extubation was associated with diabetes, ischaemic heart disease, higher E/E′ , left atrial area , fixed rightward curvature of the interatrial septum , and higher loss of aeration score of anterior and lateral regions of the lungs .Fifty-three participants who were intubated > 48 h and deemed by the treating intensivist ready for extubation underwent a 60-min pre-extubation weaning trial (pressure support ≤ 10 cmHFailed extubation in mechanically ventilated patients is more prevalent if markers of left ventricular diastolic dysfunction and loss of lung aeration are present. Weaning failure is defined as failing a spontaneous breathing trial or developing a post-extubation respiratory distress that requires re-intubation or non-invasive ventilation within 48 h following extubation . WeaningIdentification of reliable predictors of weaning failure may represent potential avenues of treatment that could reduce the incidence of weaning failure and its associated morbidity. Unfortunately, the pathophysiology of weaning failure is complex and is incompletely understood. Known risk factors of weaning failure have considerable crossover, especially those related to the heart, lungs and diaphragm. Weaning is comparable to a cardiac stress exercise where it is likely to increase the heart rate, the pulmonary artery occlusion pressure, which results in myocardial stretch and may increase cardiac output . The myoUltrasound of multiple organ systems is becoming more commonplace in the intensive care unit (ICU) setting. Ultrasound has been used to identify cardiac, respiratory or diaphragmatic risk factors of weaning failure , 11, 13.The primary aim of this pilot study was to determine which ultrasound, or clinical and biochemical indicators, were associated with weaning failure. Data from this pilot study will be used to construct future clinical trials.This single-centre, prospective observational pilot study was conducted at a 15-bed, level-III ICU that receives approximately 1500 admissions of medical and surgical presentations per year.Recruitment was performed between June 2014 and April 2016, when the primary researcher was available (convenience sampling). Participants aged 18 years or older who were mechanically ventilated for longer than 48 h and considered ready for extubation by the treating intensivist were considered eligible for recruitment. Participants were excluded if they had a diagnosis of brain death, were ventilating through a tracheostomy or if extubation was for palliation. Written informed consent was obtained from the person responsible for decision-making on behalf of the patient.Participants were considered eligible for inclusion when participants fulfilled the criteria for weaning from mechanical ventilation defined below and authorized by the treating intensivist Fig. . After i2O is an acceptable practice in our unit and a spontaneous breathing trial using T-tube is not mandated for weaning [2 ≤ 30%; pressure support ≤ 10 cmH2O; PEEP ≤ 5 cmH2O; tidal volume ≥ 5 ml/kg; respiratory rate < 35 breaths/min; requirement of low inotropic or vasopressor support; light level of sedation (Richmond Agitation Sedation Score between − 2 and + 2) [2O if required, to achieve a respiratory rate < 35 breaths/min and a tidal volume of ≥ 5 ml/kg [2O during the trial.Pressure support is a spontaneous mode of ventilation where the patient breathes spontaneously and the ventilator supports the breathing with a preset pressure value for every breath. Decremented pressure support ventilation is the standard mode of weaning in our unit. Extubation at pressure support up to 10 cmH weaning –20. The and + 2) ; ability 5 ml/kg . Positiv2 partial arterial pressure > 50 mmHg, or an increase in CO2 partial arterial pressure by ≥ 8 mmHg, pH < 7.32 or a decrease in pH by ≥ 0.07 pH units, RSBI > 105 breath/min/l, respiratory rate > 35 breaths/min, heart rate > 140 beats/min or increased by ≥ 20%, systolic blood pressure > 180 mmHg or increased by ≥ 20%, systolic blood pressure < 90 mmHg or new cardiac arrhythmias. After the completion of the weaning trial, the treating intensivist reviewed the participant for final assessment before extubation. The treating intensivist was blinded to the ultrasound findings. The decision whether to extubate the participant was determined by the treating intensivist irrespective of the weaning trial outcome. Failed extubation was defined as the requirement for re-intubation, non-invasive ventilatory support or death within 48 h after extubation.The weaning trial was considered failed if the following criteria were observed during the trial: excessive diaphoresis, Richmond Agitation and Sedation Score of ≤ − 3 or ≥ + 3, evidence of increasing respiratory effort , arterial oxygen partial pressure ≤ 60 mmHg or oxygen saturation < 90% on fractional inspired oxygen ≥ 0.4, COE), late diastolic trans-mitral flow velocity wave (A), early diastolic mitral annulus velocity E′ , E/A, E deceleration time, E/E′ , who held a recognized ultrasound certification and competence in TTE and an appropriate training and experience in lung and diaphragm ultrasound. The ultrasound machine used was a Vivid E9 . Cardiac ultrasound was performed using sector phased array 3Sc-RS cardiac probe (frequency range of 1.3–4.0 MHz). The left ventricular systolic function was assessed by measuring the ejection fraction, using bi-plane Simpson’s method of discs, and/or acquisition 2-D and M-Mode measurements at the base of the left ventricle (Teichholtz equation), depending on the quality of the images, as per the recommendations from the American Society of Echocardiography (ASE) [Lung and diaphragm ultrasound was performed using the curved array 4C-RS probe (frequency range of 1.8–6.0 MHz).Lung ultrasound was performed on all participants in a semi-recumbent position at 30°–50° using the six-zone method of each lung as described by Gargani  and VolpThe lateral approach was used to image the diaphragm, with the participants in a supine and head-up position at 30°–50° Fig. . The samReliability of ultrasound measurements of the heart, lungs and diaphragm was assessed by measuring the interobserver variability between two observers with appropriate training and experience in these measurements. Digital images of at least three cardiac cycles and three respiratory cycles for each standard view were assessed off-line using Synapse Cardiovascular software . The mean difference and limits of agreement (± 2 SDs of the difference) between the two observers was recorded. We considered the agreement between observers to be acceptable if the limits of agreement were less than 20% of the mean value of the variable being measured for continuous data.n and % for categorical variables and as median and interquartile range for continuous variables. Comparison of quantitative variables was performed using independent samples t test or Mann–Whitney test. Comparison of categorical data was performed using Fisher’s exact test. In order to determine the key predictors of successful extubation, odds ratio (OR) was obtained for each variable using univariate binary logistic regression. Due to the small sample size and therefore increased risk of Type II error, and also to reduce risk of Type I error due to multiple pairwise comparisons, the p value for significance is defined as p < 0.01. As the effect size for the ultrasound endpoints was not known, recruitment was based on a time period not exceeding 2 years, and with a maximum of 80 participants for the pilot study. All analyses were performed in SPSS version 23 (IBM Corp.).Patient characteristics were summarized as Of the 58 participants screened during the study period, five did not meet inclusion criteria: two participants had a tracheostomy, one participant died from septic shock and two participants were extubated without informing the investigators, and were not recruited. This left 53 participants for data analysis, two-thirds of whom were male. Sepsis (38%) was the most common admission diagnosis. Other diagnoses included post-surgical  (15%), drug overdose (13%), gastrointestinal disease  (12%), cardiac arrest (8%), neurological disease  (6%) acute cardiogenic pulmonary oedema (4%) and metabolic disorder (hyponatremia and diabetic ketoacidosis) (4%).2O. Pressure support received during weaning trial was zero (60%), 5–7 cmH2O (15%) and 8–10 cmH2O (25%). Fifty patients passed the weaning trial (94.4%) and three participants failed the weaning trial (5.6%). The treating intensivists, however, decided to extubate all 53 patients. Of the three participants who were extubated despite failing the weaning trial, two participants (systolic blood pressure of 200 mmHg and agitation score of + 3) were successfully extubated and one participant  failed extubation. Of the 50 participants who passed the weaning trial and were extubated, 40 (80%) participants were successfully extubated. Of the total 53 participants, 11 (20.7%) participants failed extubation over the subsequent 48 h. Two of the 11 (18%) participants that failed extubation were re-intubated and the remaining nine (82%) received non-invasive ventilation. The reasons for failure of extubation as reported by the treating team were pulmonary oedema [All 53 recruited patients followed the weaning trial protocol. All 53 patients received PEEP of 5 cmH–7 cmH2O 5% and 8––7 cmH2O 5% and 8–p = 0.01), pre-existing diabetes mellitus , higher respiratory rate  and RSBI . BNP was not associated with success or failure of extubation. There was no group separation for ICU and hospital length of stay. Two participants who failed extubation died and three participants who were successfully extubated died during their hospitalization.The participant demographic data are shown in Table p = 0.001), higher E/E′  and larger left atrial area .The cardiac, lung and diaphragm ultrasound findings, RSBI and BNP are shown in Table p = 0.007). The magnitude of diaphragmatic movement was not associated with success or failure of extubation.Higher loss of aeration score of the anterior and the lateral lung regions was associated with failed extubation , loss of aeration score of the left and right anterior and lateral regions, and increased RSBI. Interatrial septal fixed curvature and lung ultrasound findings appear promising and may aid in decision-making for extubation, as they are easily and quickly assessed, even in operators with limited echocardiographic experience. However, these results need to be verified in a larger study. The value of combined heart and lung ultrasound is that the physician extends their clinical evaluation to both the cardiac and respiratory systems to identify pathology. In some participants, pathology was confined to either the heart or lungs, and in others, pathology existed in both systems. Further, adding lung findings to heart ultrasound can act as a measure of severity. Systolic or diastolic failure patterns on heart ultrasound, for example, will have a greater severity if there is evidence of interstitial oedema on lung ultrasound, and more so is present in both upper and lower lobes.Of the clinical and ultrasound indicators in this pilot study, we determined that the most likely parameters which could be useful to help predict failed extubation are those which are related to diastolic dysfunction (left atrial area, Interestingly, participants who were older with diabetes and ischemic heart disease had greater incidence of extubation failure when compared to those who were successful. Such association between weaning failure and diabetes was also reported in a similar study . AlthougOur study particularly focused on imaging the heart, lung and the diaphragm although only during the weaning trial just before extubation. We believe that ultrasound may provide an opportunity for the intensivist to optimize the patient’s cardiac and respiratory function before extubation, and perhaps modify the weaning mechanism, such as transitioning those at risk to non-invasive ventilation before discontinuing the ventilatory support , 33.E/E′ is greater than 7.8 [E/E′, ejection fraction had no impact on weaning outcome. Recent published data have demonstrated a positive association between the echocardiographic measurements of diastolic failure, in particular E/E′, and weaning failure [E/E′ is a marker of left atrial pressure, and that of left ventricular diastolic pressure. E/E′ correlated well with pulmonary artery occlusion pressure [E/E′ range of cut-off values of 7–14 has been suggested for determining patients at risk of failing weaning from mechanical ventilation [Our data do not allow us to determine why diastolic dysfunction is associated with weaning failure. However, it is reasonable to assume that patients with raised left atrial pressure may be more likely to develop pulmonary venous congestion as the hemodynamic stress associated with weaning increases. A study by Caille et al. suggested that patients are more likely to fail weaning when their left ventricular ejection fraction is lower than 35% and than 7.8  showed t failure , 34. E/Epressure . Howeverpressure . E/E′ ratilation , 34. In tilation .Fixed rightward curvature of interatrial septum was a prominent finding in the failed extubation group. Assessment of interatrial septal movement is an easy technique to perform to obtain a visual estimation of the left atrial pressure state. Royse et al.  found thLeft atrial enlargement is an indicator of severity and chronicity of diastolic dysfunction and is associated with increased left atrial pressure . HoweverLung ultrasound is a non-invasive and easily performed bedside test. It has clinical and practical advantages over conventional chest radiography , 38. BesMechanical ventilation may induce diaphragmatic dysfunction from muscle disuse, particularly in prolonged mechanical ventilation . DiaphraOn current practice, the prediction of successful weaning and readiness for extubation is assessed using clinical and biochemical parameters including the degree of respiratory support, respiratory rate, tidal volume, RSBI and arterial blood gas analysis. RSBI is a surrogate marker of quality of breathing during weaning from mechanical ventilation. It is defined as the ratio between respiratory rate and tidal volume where a value greater than 105 breaths/min/l predicts patients at high risk of failing weaning , 43. HowThis is a pilot study, and therefore it can only be used to identify potentially useful parameters to aid clinical decision-making. The study was based on convenience sampling, which was subject to the availability of the research sonographer. In contrast to some previously published studies, our study protocol did not interfere with the clinician’s extubation decision, and all participants proceeded to extubation regardless of weaning trial outcome. In the lung ultrasound, we did not image the postero-superior areas due to difficult windows in supine ventilated patients, and the upper lobe can be visualized from the anterior approach. It is possible, however, that some upper lobe pathology may have been missed. The results of this study can be further tested by a larger prospective study in a high-risk population that perhaps are older with history of diabetes and/or ischemic heart disease and with a clinical diagnosis of cardiac.Failed extubation in mechanically ventilated patients is more prevalent if markers of left ventricular diastolic dysfunction and loss of lung aeration are present.