To present and validate a method for automated extraction and analysis of the temporal evolution of the mitral valve (MV) vortex ring from MR 4D‐flow data.Q criterion‐based identification and tracking of MV vortex ring core and region within the left ventricle (LV). The 4D‐flow data of 20 subjects  were used to validate the algorithm against visual analysis as well as to assess the method’s sensitivity to manual LV segmentation. Quantitative MV vortex ring parameters were analyzed with respect to both their differences between healthy subjects and patients and their correlation with transmitral peak velocities.The proposed algorithm uses the divergence‐free part of the velocity vector field for The algorithm successfully extracted MV vortex rings throughout the entire cardiac cycle, which agreed substantially with visual analysis (Cohen’s kappa = 0.77). Furthermore, vortex cores and regions were robustly detected even if a static end‐diastolic LV segmentation mask was applied to all frames . Early diastolic MV vortex ring vorticity, kinetic energy and circularity index differed significantly between healthy controls and patients. In contrast to vortex shape parameters, vorticity and kinetic energy correlated strongly with transmitral peak velocities.An automated method for temporal MV vortex ring extraction demonstrating robustness with respect to LV segmentation strategies is introduced. Quantitative vortex parameter analysis indicates importance of the MV vortex ring for LV diastolic (dys)function. While an algorithm for automated λ2 thresholding in the segmented heart at peak diastolic inflow has been proposed,As there is no universal definition of a vortex,Q criterion‐basedWe present a method for automated extraction of the temporal evolution of the MV vortex ring from 4D‐flow MRI data. The proposed algorithm uses the divergence‐free part of the velocity vector field for 22.1The 4D‐flow data of 10 healthy controls  without history of cardiac disease and 10 patients with chronic IHD  were included in the analysis (further details on the study population are given in the Supporting Information). The data were acquired in a prospective study , which was approved by the local ethical review board. All participants provided written informed consent.2.23, bandwidth = 605 Hz/pixel, GRAPPA with parallel acquisition factor of 2 and acquisition of external reference lines for sensitivity estimation, and temporal resolution = 41.8 ms interpolated to 30 cardiac frames. Two‐fold averaging was used to reduce breathing artifacts, resulting in an acquisition time of 44 ± 9 seconds per slice and 13.3 ± 3.4 minutes for the stack of slices covering the LV. Whereas the data of healthy controls were acquired without contrast‐medium administration, 0.2 mmol/kg of gadobutrol  was administered to patients with IHD 15 to 20 minutes before 4D‐flow imaging. Flip angles were set to 12° and 18º‐20° for healthy subjects and patients with IHD, respectively.All subjects underwent 4D‐flow imaging at 3 T  in the supine position and under free breathing, using an 18‐channel body array coil together with 12 elements of a 32‐channel spine coil. A stack of slices in three‐chamber‐view orientation covering the LV was acquired using a 2D retrospectively electrocardiographically‐gated phase‐contrast sequence with three‐directional simple four‐point velocity encoding.2.34DFlow, Siemens Healthcare, Erlangen, Germany), which was further used for manual segmentation, measurement of transmitral flow parameters, as well as vector field and streamline visualization for visual analysis. The LV blood pool, including the LV outflow tract as well as papillary muscles and trabeculae, was manually segmented in all 30 cardiac frames on multiplanar reformatted short‐axis 4D‐flow magnitude images with a slice distance of d = 3.4 mm. Peak velocities of early and late diastolic transmitral inflow  were determined from the maximum velocity‐time curve measured at the MV leaflet tips and are denoted here by vE and vA. Multiplanar reconstructed 2D velocity vector fields and 3D streamlines  were visually evaluated in each frame for the presence of an MV vortex ring  of the acquired velocity fields was performed by dedicated prototype software , based on the algorithm presented by Kräuter et alAll further data processing was automatically performed by in‐house software implemented in 2.4Q criterion) is calculated and used to identify vortex candidates in the LV. Third, the MV vortex ring core is detected and traced over time. Finally, the MV vortex region is determined using streamlines seeded near the vortex core.The pipeline for automated MV vortex ring extraction consists of four steps Figure . First, 2.4.1v on a bounded or unbounded domain can be uniquely decomposed into a rotation‐free, a divergence‐free, and a harmonic part:According to the Helmholtz‐Hodge decomposition,d is rotation‐free (∇×d=0),r is divergence‐free (∇·r=0), andh is rotation‐free and divergence‐free (∇×h=0 and∇·h=0). As we are aiming for vortex detection, only the part of the vector field containing information about rotation is of interest. To calculate the divergence‐free vector field, it can be represented as the curl of a vector potentialwherewhich leads to the Poisson equationΨ|∂Ω=0, the equation system can be uniquely solved.Ψ using minimum norm least squares. The divergence‐free vector field is calculated fromΨ according to Equation  are determined according toTo identify regions of strong vortical flow, frame‐specific N is the number of cardiac frames, iQ is the Q field in frame i, andrQnmax is the location of the maximum Q value in frame n  is used to calculate candidate factors fc, representing the probability that each vortex region belongs to the MV vortex ring as follows:As applying the frame‐specific thresholds to the dmax is the maximal distance of the vortex region to the location of the maximum of the w1 field in LV long‐axis direction, and M is the number of vortex region voxels. The two vortex regions, if present, with highest probability of belonging to the MV vortex ring and a dmax that is smaller than two times the minimum dmax of all vortex regions, are selected as vortex candidates.where 2.4.3Q point inside a vortex candidate region. In the predictor step, the vortex core is elongated in the direction of the local vorticity vector yielding the predictor point. In the corrector step, this point is corrected to the maximum Q point (= corrector point) on a plane that is perpendicular to the vorticity vector at the predictor point using a pattern‐search algorithm, as suggested by von Spiczak et al.A modified version of the predictor‐corrector methodQ time curve  was calculated as the sum of the vortex region voxels times the voxel volume.Absolute and relative kinetic energy (Ekin) were computed from the velocity magnitude in each MV vortex ring voxel, assuming a density of blood of ρ = 1060 kg/m3.Ekin was calculated by normalization to the MV vortex ring volume.Angle to LV long axis (α) was determined by fitting a plane to the MV vortex ring core and measuring the angle to the direction normal to the LV short‐axis plane.Circularity index (CI), as defined by Elbaz et al,The following parameters describing the MV vortex ring were automatically computed for each frame:2.6d of short‐axis segmentation  to all 30 cardiac frames , third (3d), fourth (4d), fifth (5d), and sixth (6d) short‐axis slice, leading to a maximum slice distance of 20.4 mm. Furthermore, segmentation variability was simulated by erosion (maskerode) and dilation (maskdilate) of the reference segmentation mask by one voxel in each frame  and MATLAB. The Cohen’s kappa coefficient (κ) was used for comparison of MV vortex ring existence in each frame between visual and automated analysis as well as for pairwise MV vortex ring existence comparisons of all segmentation masks with the reference condition. In MV vortex ring frames common to both segmentation masks, overlap ratios of vortex core and vortex region were assessed using the Dice similarity coefficient (DSC).t‐test. Mean values of continuous variables were compared between healthy subjects and patients with IHD using unpaired t‐test. Dependencies of early and late diastolic MV vortex ring parameters on respective transmitral peak velocities and systolic LV function parameters were assessed by Pearson correlation coefficient (r). Pearson’s r was interpreted according to the following categorization: “poor” ≤ 0.5; 0.5 < “good” ≤ 0.7; 0.7 < “strong” ≤ 0.9; and “excellent” > 0.9. A P value < .05 was considered significant.Statistical analysis was performed with 33.1vol, α, and CI) did not exhibit biphasic behavior.The proposed algorithm successfully extracted the temporal evolution of the MV vortex ring in healthy subjects and patients with IHD and determined vortex region–based as well as vortex core–derived parameters. Two periods of MV vortex ring existence were identified Figure : the fir3.2κ = 0.77 , Table P < .01; A vortex ring bias = 28 ± 14 ms, P < .01), MV vortex ring dissolution time differed between visual and automated detection only for E vortex ring .Automated and visual analysis agreed substantially with respect to MV vortex ring existence in each frame  for maskerode. While the other segmentation masks also yielded sporadic statistically significant differences, their absolute mean errors were small . Comparing the average errors of different MV vortex ring parameters, maximum and mean vorticity were found to be the least sensitive to segmentation variation. Furthermore, all parameters were more stable for A vortex ring than for E vortex ring.In the reference condition, 840 ± 118 short‐axis slices per subject were manually segmented. All segmentation experiments yielded E and A vortex rings in each subject. Table 3.4Early and late diastolic peak values of MV vortex ring parameters for healthy subjects and patients with IHD are given in Table vE,healthy = 67 ± 7 cm/s, vE,IHD = 58 ± 12 cm/s, P = .07; vA,healthy = 61 ± 15 cm/s, vA,IHD = 67 ± 11 cm/s, P = .28); however, the E‐to‐A‐wave peak velocity ratio differed . In contrast to peak values of MV vortex ring shape parameters, peak values of velocity‐derived MV vortex ring parameters correlated strongly with the corresponding E and A wave peak velocities . Correspondingly, CI was higher at E wave peak velocity frame than at A wave peak velocity frame . Neither volume nor α, on the other hand, differed significantly between E wave peak velocity frame and A wave peak velocity frame .For healthy subjects, early and late diastolic peak values of MV vortex ring parameters did not differ significantly, except for 4We present an automated method for temporal MV vortex ring core and region extraction from 4D‐flow data allowing for quantitative vortex property assessment in healthy and diseased subjects. In particular, we demonstrate (1) substantial agreement with visual analysis, (2) robustness to manual LV segmentation speed‐up strategies, and (3) strong correlations between MV vortex ring parameters and transmitral peak velocities as well as differences in early diastolic MV vortex ring properties between healthy controls and patients with IHD.4.1As MV vortex rings were detected in both healthy controls and patients with severe IHD, the proposed algorithm can be considered a robust method for automated MV vortex ring extraction. The identification of MV vortex ring formation during early and late diastolic filling, with typical vortex dissolution during diastasis, is in accordance with visual observations by Elbaz et al.Automated calculation of MV vortex ring core and region parameters in each frame permits analysis of parameter‐time curves and their characteristics, such as the maxima or minima of parameters. While velocity‐derived MV vortex ring parameters resemble the biphasic time course of E and A wave velocities, no distinct patterns for temporal evolution of MV vortex ring volume, circularity, or angle to LV long axis were identified. This can probably be attributed to the fact that the evolving MV vortex ring adapts to intraventricular structures4.2Automatically and visually detected MV vortex rings showed good agreement. The differences in MV vortex ring onset times can be explained by the difficulty of identifying subtle vortex structures visually. In frames at the end of the MV vortex ring evolution process, in which the MV vortex ring breaks and twists open, there were few cases where visual analysis detected an MV vortex ring but automated analysis did not, and the other way around. It is debatable whether the structures in these frames can still be considered MV vortex rings.4.3end‐dia resulted in acceptable MV vortex ring core and region extraction scores and yielded small MV vortex ring parameter errors. This finding is in line with the overall observation that MV vortex ring extraction is less sensitive to over‐segmentation than to under‐segmentation, which is to be expected, as in the latter case parts of the MV vortex ring core and region might be missed.Automated MV vortex ring extraction was found to be robust when using accelerated manual LV segmentation approaches. According to the results of the slice distance experiment, segmentation time of 4D‐flow magnitude images can be reduced by segmenting fewer LV short‐axis slices. In particular, automated MV vortex ring extraction might be feasible with registered LV contours, such as from balanced SSFP cine short‐axis images , for which automated segmentation algorithms exist.4.4Apart from shape and position parameters,CI confirmed that in healthy subjects E vortex rings have a more circular shape than A vortex rings.CI values at E and A wave peak velocity frames were within the previously published normal range.CI between healthy and diseased subjects, as reported by Calkoen et alAutomatically determined −1) are in a similar range as the 3D mean vorticity in our healthy controls. Kim et alVorticityThe observed differences in early diastolic MV vortex ring properties between healthy controls and patients with IHD supports the assumption that MV vortex ring alterations are associated with LV dysfunction. The strong correlations of velocity‐derived MV vortex ring parameters with their corresponding E and A wave peak velocities together with the weaker correlations with systolic LV function parameters suggest that they could serve as indices of LV diastolic function.4.5No reference standard exists for MV vortex ring detection. However, visual analysis is the most intuitive way of observing a vortex, and was therefore chosen as the reference method in this study. z‐direction than the minimum spatial resolution (3 × 3 × 3 mm3) recommended by the 4D‐flow MRI consensus statement.4D‐flow data have limited spatial and temporal resolution, which might have contributed to the observation of U‐shaped and bracket‐shaped rather than toroid MV vortex rings. In particular, the spatial resolution of the 4D‐flow data of the present study is lower in the4D‐flow data in patients were assessed after contrast agent, whereas no contrast agent was applied in healthy controls. Even though they affect the SNR of the data, measured velocities and velocity fields should not be affected by contrast agent.Manual segmentation was performed with prototype software that is optimized for 4D‐flow data preprocessing and visualization rather than segmentation, which explains the long manual segmentation times per subject. Segmentation time might be substantially decreased with suitable 4D‐flow data segmentation software.The number of healthy controls and patients with IHD was small, and only one patient group was included. However, the focus of this study was to provide a proof of concept of automated MV vortex ring extraction in healthy and diseased subjects and, as discussed previously, segmentation could be accelerated substantially to enable investigations in larger patient cohorts.5A method for automated extraction of the temporal evolution of MV vortex ring core and region from 4D‐flow data is introduced, demonstrating good agreement with visual analysis and robustness with respect to LV segmentation. Differences of quantitative MV vortex ring parameters between healthy and diseased subjects as well as strong correlations with peak inflow velocities indicate the potential of MV vortex ring properties to characterize LV function and dysfunction.Gert Reiter is employed by Siemens Healthcare Diagnostics GmbH.TABLE S1 Systolic LV function parameters for healthy controls and IHD patients. Note: End‐diastolic volume (EDV), end‐systolic volume (ESV), ejection fraction (EF), stroke volume (SV) and cardiac output (CO) were derived from stacks of balanced SSFP (bSSFP) short‐axis cine series together with bSSFP two‐chamber and four‐chamber view cine series for mitral valve (MV) base plane modeling using dedicated software . The P value refers to unpaired t‐test. Abbreviation: ns, not statistically significantTABLE S2 Correlogram of systolic LV function parameters with early and late diastolic peak values of MV vortex ring parameters for all subjects (N = 20). Note: The Pearson correlation coefficient is specified with its 95% confidence interval. Abbreviation: ns, not statistically significantClick here for additional data file.


High-grade inflammation may play a pivotal role in the pathogenesis of left ventricular (LV) dysfunction. Evidence to support a role of systemic inflammation in mediating impaired LV function in experimental models of rheumatoid arthritis (RA) remains limited. The aim of the present study was to determine the effects of high-grade systemic inflammation on LV diastolic and systolic function in collagen-induced arthritis (CIA).To induce CIA, bovine type-II collagen emulsified in incomplete Freund’s adjuvant was injected at the base of the tail into 21 three-month old Sprague Dawley rats. Nine-weeks after the first immunisation, LV function was assessed by pulsed Doppler, tissue Doppler imaging and Speckle tracking echocardiography. Cardiac collagen content was determined by picrosirius red staining; circulating inflammatory markers were measured using ELISA.Compared to controls (n = 12), CIA rats had reduced myocardial relaxation as indexed by lateral e’  and e’/a’  and increased filling pressures as indexed by E/e’. No differences in ejection fraction and LV endocardial fractional shortening between the groups were recorded. LV global radial and circumferential strain and strain rate were reduced in CIA rats compared to controls. Higher concentrations of circulating inflammatory markers were associated with reduced lateral e’, e’/a’, radial and circumferential strain and strain rate. Greater collagen content was associated with increased concentrations of circulating inflammatory markers and E/e’.High-grade inflammation is associated with impaired LV diastolic function and greater myocardial deformation independent of haemodynamic load in CIA rats. Heart failure with a preserved ejection fraction (HFpEF) accounts for more than 50% of all heart failure cases and is associated with an increased morbidity and mortality . There aHypertension, diabetes mellitus and obesity comprise traditional cardiovascular risk factors that are associated with diastolic dysfunction . HoweverChronic systemic inflammation is also associated with heart failure with a reduced ejection fraction (HFrEF) in the general population . Higher All experimental procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals, Eighth Edition, updated by the US National Research Council Committee in 2011 and were approved by the Animal Ethics Screening Committee (AESC) of the University of the Witwatersrand (AESC number: 2017/03/21C). Thirty-three, three-month-old male Sprague Dawley rats (480-510g) were studied. Rats were housed individually in cages in a temperature-controlled room with a 12-hour light-dark cycle and allowed free access to food and water. During the two week acclimatisation period, blood pressure (BP) was measured twice a week and body weight, paw thickness and articular index scores were measured once a week. Following acclimatisation, rats were randomly assigned to the control group  that had no intervention, or the collagen induced arthritis group  that were exposed to high-grade inflammation. Body weight, paw thickness, articular index scores and BP were measured once a week for nine weeks. Echocardiography was performed and blood samples were obtained at the end of the nine week study period.Experimental arthritis was induced in rats as previously described . BrieflyBlood pressure was measured weekly using the tail-cuff technique . Each rat was placed in a restrainer with a cuff attached to a heated tail. Measurements were taken at midday to avoid diurnal variation.-1) and xylazine (5mg.kg-1). Echocardiography was performed by an experienced observer, according to the American Society of Echocardiography conventions [Nine weeks after the first immunisation, rats were anaesthetised with an intraperitoneal injection of ketamine  and late (A) diastolic inflow velocity were obtained with the sample volume placed at the mitral valve leaflet tip and expressed as E/A as a marker of relaxation. To determine diastolic function using tissue Doppler imaging (TDI), peak myocardial tissue lengthening velocities during early (e’) and late (a’) diastole were recorded at the lateral mitral annulus in the apical four-chamber view. Data were expressed as e’ , e’/a’  and E/e’ (an index of LV filling pressure).LV pump and myocardial systolic function was determined by calculating LV ejection fraction (EF) using the Teichholz method  and LV e-1 and xylazine 10 mg.kg-1 followed by thoracotomy. After thoracotomy, blood was sampled and allowed to clot for 2 hours at room temperature. Blood was centrifuged and serum was collected and stored at -80°C until assayed. Serum concentrations of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1β (IL-1β) and C-reactive protein (CRP) were measured by ELISA using commercially available ELISA kits according to the instructions of the manufacturer . Each sample was measured in duplicate. The lower detection limit for TNF-α, IL-6, IL-1β and CRP were 78.13 pg/ml, 62.50 pg/ml, 31.2 pg/ml and 0.31 ng/ml respectively, all with coefficients of variation of <10%.Rats were sacrificed with an intraperitoneal injection of ketamine 200 mg.kgCardiac tissue samples were fixed in 10% buffered formalin and routinely processed for paraffin embedding. Five μm thick tissue sections were deparaffinised, rehydrated and stained with a 0.1% Sirius Red solution dissolved in aqueous saturated picric acid for 60 min at room temperature. After washing in acidified water, slides were dehydrated and mounted with DPX mounting. The tissue sections were analysed using a Zeiss Axioskop 2 Plus microscope equipped with a Zeiss AxioCam . Tissue sections viewed under bright-field and polarized light were obtained with a 10x objective lens (x100 magnification). Using ImageJ software, the collagen area fraction was calculated for each tissue section by dividing the collagen area by the total tissue area.Data are expressed as means ± SD. Data analysis was performed using SAS software version 9.4 . Unpaired, two-tailed t-tests were performed to determine differences in echocardiographic measures and inflammatory markers between the CIA and control groups. Associations between diastolic and systolic function parameters and inflammatory markers were determined by Pearson’s correlation coefficients. A P value < 0.05 was considered statistically significant.The onset of arthritis in the CIA group occurred within 21–28 days after the first immunisation. Clear signs of inflammation including erythema, oedema and joint rigidity were observed in the CIA group . CompareThere were no differences in stroke volume (p = 0.31), ejection fraction (p = 0.71) or endocardial fractional shortening (p = 0.60) between the groups . Global In segmental analysis in the short-axis radial strain, circumferential strain, radial strain rate and circumferential strain rate were predominantly impaired at the anterior-septal, anterior and septal LV segments in the CIA group compared to controls  or endocardial fractional shortening .In the present study, CIA in adult, male Sprague Dawley rats caused impaired LV relaxation (decreased e’) and increased LV stiffness (decreased e’/a’) and LV filling pressures (increased E/e’). The diastolic abnormalities were noted despite a normal blood pressure and unaltered mitral inflow patterns (E/A). Although LV chamber pump function (ejection fraction) and contractility  were preserved, CIA rats demonstrated early myocardial dysfunction as indexed by myocardial deformation . Elevated inflammatory cytokines were associated with impaired diastolic function (e’ and e’/a’), increased collagen content and global radial and circumferential strain and strain rate. The present findings suggest that, independent of load, LV diastolic function and myocardial deformation are adversely affected when exposed to high-grade inflammation in rats.Previous cross-sectional studies have reported impaired diastolic function in RA patients with adverse inflammatory profiles –12, 14. Besides impaired active relaxation, passive myocardial stiffness contributes to the pathogenesis of diastolic dysfunction , 5. HypeGrowing evidence suggests that inflammatory cytokines mediate several cellular changes that cause abnormalities in myocardial relaxation. First, inflammation has been shown to impair the active calcium-dependent processes involved in myocardial relaxation , 38. Addin vivo mouse model of collagen antibody induced arthritis [In previous cross-sectional RA studies, inflammatory cytokines have been associated with increased myocardial deformation , 25, 26.rthritis . While trthritis . In addirthritis . In the In the present CIA investigation, myocardial deformation and motion were consistently reduced in the anterior septal, anterior and septal LV myocardial segments. The lateral LV segment was affected to a lesser extent whereas the inferior and posterior walls were unaltered. Previous studies have shown that the septal wall has a greater sensitivity to fibrosis  and incrThe current study presents with limitations. Although associations were demonstrated between circulating inflammatory markers and impaired cardiac function, the direct casual effect of inflammation on impaired cardiac function can only be implied. Future studies have to determine whether inflammation alters the cellular mechanisms responsible for the changes in LV function seen in the current study, and whether immunosuppressive drugs restore the inflammation-induced cardiac impairments. Secondly, non-invasive approaches rather than catheter-based systems were used to assess diastolic function in the present study. However, tissue Doppler indices of diastolic function were previously shown to correlate well with invasively measured LV relaxation, stiffness and filling pressures . Thirdlyin vivo with impaired LV diastolic function and greater subclinical myocardial deformation, independent of blood pressure. These findings add to the evidence that systemic inflammation may mediate myocardial remodelling leading to diastolic dysfunction and myocardial deformation. Considering the lack of adequate pharmacological therapy for the management of HFpEF, further research should determine the effect of anti-inflammatory substances in the prevention and management of HFpEF.In conclusion, the present study showed that high-grade inflammation is associated S1 FigTNF-α, tumor necrosis factor alpha; IL-6, interleukin 6; IL-1β, interleukin 1 beta; CRP, C-reactive protein. Open circles represent the correlation coefficient (r) and horizontal lines represent the 95% confidence intervals (Cl) (Pearson’s correlation).(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


More than one hundred million people reside worldwide at altitudes in excess of 2500 m above sea level. In the millions more who sojourn at high altitude for recreational, occupational or military pursuits, hypobaric hypoxia drives physiological changes affecting the pulmonary circulation, haematocrit and right ventricle (RV) [1]. Coincident with these, maximal left ventricular (LV) stroke volume (SV) falls [2], with a reduction of 20% reported after a 2-week stay at 4300 m [3]. A rise in heart rate (HR) compensates at rest and during submaximal exercise but is insufficient during maximal intensity exercise, constraining maximal cardiac output (CO). Previously, it was considered that a reduction in plasma volume or a direct effect of hypoxia on LV myocardial contractility were probably responsible [4]. More recently it has been suggested that increased RV afterload may be of greater importance [5]. S2pO on ascent to very high altitude (5100 m). These effects appear to result from reduced pulmonary vascular resistance and improved right heart function.Intravenous iron supplementation at sea level is associated with enhanced stroke volume and higher https://bit.ly/2VQX5fR To the Editor:More than one hundred million people reside worldwide at altitudes in excess of 2500 m above sea level. In the millions more who sojourn at high altitude for recreational, occupational or military pursuits, hypobaric hypoxia drives physiological changes affecting the pulmonary circulation, haematocrit and right ventricle (RV) . Coincidi.v.) iron attenuates HPV [i.v. iron would improve cardiopulmonary function during ascent to very high altitude through this action upon the pulmonary vasculature, with or without a direct effect on the heart.Hypoxic pulmonary vasoconstriction (HPV) contributes significantly to increased RV work and pulmonary hypertension during alveolar hypoxia . In healates HPV , 8, tendS2pO), and transthoracic echocardiographic parameters  were recorded at rest.We conducted a randomised, controlled, double-blind, clinical physiology study. 18 British Armed Forces personnel  volunteered; one was excluded because of abnormal baseline iron indices. Participants were randomised to receive either 1 g ferric carboxymaltose (Ferinject), or saline control, as a single infusion. 2 weeks later, participants flew to Kathmandu, Nepal, at an altitude of 1400 m, were driven to 2600 m (day 4), trekked to 3800 m (day 5), 4100 m (day 7), and then 5100 m (day 10). Serial measurements of iron indices, peripheral oxyhaemoglobin saturation .Stroke volume was estimated by multiplying LV outflow tract (LVOT) velocity-time integral (VTI) by LVOT cross-sectional area, and CO by multiplying SV and HR. Both were then normalised to body surface area in mRight ventricular systolic pressure (RVSP) was estimated from the peak velocity of the tricuspid regurgitation jet , 5, 7–9.versus controls were as follows: mean±sd age 35.5±8.2 versus 36.1±7.7 years; body mass index 24.8±1.0 versus 24.6±2.0 kg·m−2; and BSA 2.02±0.06 versus 1.99±0.04 m2. No adverse infusion-related events occurred. One participant in the control group did not ascend beyond 4100 m due to severe gastrointestinal symptoms; all available data for this participant were included in the analysis.The groups were well matched at baseline. Comparisons for the iron group Changes in iron indices, haematological parameters and cardiopulmonary variables are illustrated in S2pO seen with increasing altitude . Iron also abolished the normal fall in SV observed with increasing altitude. The mean between-group difference in the change in stroke volume index (SVI) was 6.2 mL·m−2 .The prior administration of iron significantly attenuated the progressive fall in In the control group, LIMP, RIMP and TAPSE all worsened significantly with increasing altitude. LIMP rose by 0.08 , RIMP rose by 0.31 , and TAPSE fell by 0.55 cm . When comparing the iron group with controls, the degree of impairment in RIMP and TAPSE was reduced by 0.14  and 0.41 cm , respectively. However, the iron group showed no difference in the deterioration in LIMP  nor the rise in RVSP on ascent .r=−0.72; p=0.003), implying a close relationship between increased RV afterload and falling SV.Interestingly, we found that iron supplementation was associated with augmented SV in the absence of a difference in RVSP. Had PVR remained similar in both groups, the higher SV of the iron group would be expected to have associated with a higher RVSP. In fact, RVSP responses were similar and there appeared to be a trend towards a lower PVR in the iron group, although this was not statistically significant . However, a strong negative correlation was evident between the change in SVI and the change in PVR (Pearson's Reduced PVR might be a direct result of increased iron bioavailability, as previously described , 8, or mvia an action on the hypoxia inducible factor pathway within carotid body glomus cells [An alternative explanation would be that iron acted to augment the ventilatory response to hypobaric hypoxia. We were not able to measure ventilation as part of the expedition. Whilst there is good reason to believe iron bioavailability might affect pulmonary ventilation us cells , no humaus cells , 12. MorThe links between iron, erythropoiesis and oxygen homeostasis are complex . Erythroi.v. iron therapy is well established in chronic heart failure [A role for  failure . Our fin10.1183/13993003.02285-2019.Shareable1This one-page PDF can be shared freely online.ERJ-02285-2019.ShareableShareable PDF


Background: The QRS-T angle from the surface EKG is a promising prognostic marker in patients with coronary artery disease. Cardiovascular magnetic resonance (CMR) imaging with late gadolinium enhancement (LGE) offers high resolution imaging of myocardial damage. We investigated the association of the QRS-T angle and the extent of myocardial damage as assessed by LGE in patients with acute ST-segment myocardial infarction (STEMI)Methods: 169 patients with STEMI obtained a standardized digital 12-lead EKG on admission for the calculation of the QRS-T angle and underwent CMR imaging for analysis of infarct size by LGE within the first week. Patients were divided into groups: (1) abnormal QRS-T angle ≥ 90 degree and (2) QRS-T angle < 90 degree.Results: Patients with a QRS-T angle of 90 degree or more had larger infarcts  and lower ejection fraction .Conclusion: The extent of myocardial damage as measured by the gold standard LGE is associated with a larger QRS-T angle calculated from the surface EKG. Early restoration of epicardial blood flow by percutaneous coronary intervention (PCI) or thrombolysis is the gold standard of ST-segment elevation myocardial infarction (STEMI) treatment Apart from clinical risk scores, biomarkers and imaging it would be extremely helpful to establish a simple parameter from the routine surface ECG for risk stratification in acute STEMI ≥90°) seems to correlate with electrical instability and has been related to cardiac prognosis in several studies The QRS-T angle represents the spatial angle between the QRS loop (depolarization) and T loop (repolarization) Cardiovascular Magnetic Resonance (CMR) imaging following gadolinium contrast administration allows for high-resolution imaging of myocardial damage This study aims to investigate the correlation of the QRS-T-angle on the 12-lead surface ECG and the extent of myocardial damage in patients with acute STEMI as assessed by late gadolinium enhancement CMR.Consecutive patients admitted to the Department of Cardiology and Angiology at Elisabeth Hospital Essen from February 2015 until March 2017 with acute ST-segment elevation myocardial infarction (STEMI) were enrolled into the study. Patients obtained a standardized 12-lead digital ECG immediately on admission using a Schiller Cardiovit AT 102 plus®. Computerized values of QRS and T-wave axis were given by the Schiller AT 102 plus® software. The frontal QRS-T-angle was calculated as the absolute difference between the frontal QRS- and frontal T-wave axes. With a value greater than 180°, 360° were subtracted in order to give a continuous variable ranging from 0° to 180°.CMR imaging was performed on a 1.5 Tesla MR System  not later than 7 days after admission. MR sequences were acquired using a phased-array receiver coil during end-inspiratory breathholding and in line with the recommendations of the Society of Cardiovascular Magnetic Resonance (SCMR) Cine and LGE images were evaluated blinded to the clinical data by two experienced observers in consensus. LV function was analyzed by outlining epicardial and endocardial borders on the short axis SSFP sequences. Papillary muscles were excluded from analysis. Left ventricular volumes and ejection fraction were derived from contour summation. The extent of late gadolinium enhancement was assessed on long and short axis contrast images by using the 17-segment model of the LV. Typical expansion of LGE in patients with acute myocardial infarction (STEMI) is defined as areas of high signal intensity progressing from the subendocardial myocardial layer. Areas with ischemic infarct scar were defined as enhanced with a signal intensity above at least five SD as compared to non-infarcted remote myocardium. The presence and transmurality of infarcts were scored using the 17-segment model and a 5-point scala per segment . The total infarct size as expressed as percentage of LV mass was calculated as follows: sum of enhanced segments and their transmurality score (LGE score) divided by 17 segments multiplied by the maximum transmurality score Statistical analyses were performed with the Excel™ software . Depending on the distribution continuous variables were expressed as means with standard deviation. Patients were divided into two groups . The two-sample t-test was chosen to analyze differences between these two groups. Pearson correlation and one-sample t-test were applied to investigate the correlation of QRS-T angle and CMR parameters in each group. P values <0.05 were considered as statistically significant.From February 2015 to March 2017, 169 patients  admitted for acute STEMI  were enrolled.Patients were divided into two groups: 1) patients with a frontal QRS-T angle of 90 degree or more (n=54), (2) patients with a frontal QRS-T angle of less than 90 degree (n=114)  and the heart rate on admission EKG was higher . There was no difference between the two groups with regards to maximum creatinkinase  and maximum troponine .On CMR imaging Figure , Table 1Our study shows that in a population of STEMI patients QRS-T angle on the surface EKG correlates with infarct size on contrast-enhanced CMR.Previously several studies have been able to demonstrate the prognostic value of QRS-T angle in different patient populations. In a general Rotterdam population of 6,134 patients Kors et al. found an odds ratio of 5.6 for sudden cardiac death, which was superior to standard EKG indicators of adverse events such as ST depression and T wave inversion Several ECG signs have been evaluated against distribution, transmurality and extent of late gadolinium enhancement on CMR following gadolinium contrast administration: In acute STEMI the resolution of ST-segment elevation, a marker of successful reperfusion therapy, relates to LGE and prognosis The concept of validating EKG parameters by scar (LGE) rather than left ventricular morphology, hypertrophy and function has also been investigated in the setting of non-ischemic cardiomyopathies: In hypertrophic cardiomyopathy late gadolinium enhancement is a strong and independent prognosticator of cardiac death For a prognostic EKG marker that represents myocardial depolarization and repolarization in the way the QRS-T angle does, the correlation to myocardial pathology on CMR is particularly useful. To the best of our knowledge, this is the first study that relates QRS-T angle in patients with acute myocardial infarction (STEMI) to CMR function and scar.Several non-invasive parameters that could help risk stratify patients with acute myocardial infarction are used in clinical routine. These include left ventricular ejection fraction, left ventricular volumes, several ECG parameters and detection of myocardial necrosis by contrast-enhanced cardiovascular magnetic resonance imaging. The ultimate goal in risk stratification is to identify patients who will suffer from sudden cardiac death and who need further protection, e.g. the implantation of cardioverter-defibrillator (ICD). However, up till now no single parameter has been successful to fulfill the task. In fact, due to the complex pathophysiology of ventricular arrhythmias a combination of non-invasive parameters might improve the prediction of ventricular arrhythmias in post acute MI patients. The QRS-T angle in patients with acute MI can be ubiquitously assessed and might add to clinical risk stratification in the future.In conclusion, a QRS-T angle of 90 degrees or more is associated with lower ejection fraction and greater infarct size as assessed by contrast-enhanced CMR. Prospective studies in a larger STEMI patient population with clinical follow-up should be carried out in order to further investigate the prognostic impact of the QRS-T angle and its potential implication on clinical workflow.


Chronic Chagas’ cardiomyopathy is the most severe and frequent manifestation of Chagas disease, and has a high social and economic burden. New imaging modalities, such as strain echocardiography, nuclear medicine, computed tomography and cardiac magnetic resonance imaging, may detect the presence of myocardial fibrosis, inflammation or sympathetic denervation, three conditions associated with risk of sudden death, providing additional diagnostic and/or prognostic information. Unfortunately, despite its high mortality, there is no clear recommendation for early cardioverter-defibrillator implantation in patients with Chagas heart disease in the current guidelines. Ideally, the risk of sudden cardiac death may be evaluated in earlier stages of the disease using new image methods to allow the implementation of primary preventive strategies. Chronic Chagas’ cardiomyopathy is the most severe and frequent manifestation of Chagas disease and occurs in 25–30% of infected people. Patients may develop severe clinic manifestations, such as congestive heart failure, malignant arrhythmias or thromboembolism ,2.The disease is endemic in Latin America, where it is responsible for a high social and economic burden, however, due to the migration of affected individuals and the increased number of patients infected through other forms of transmission, such as blood transfusion, organ transplantation or vertically from mother to infant, the disease has become a global health concern. Non-endemic countries have reported increasing numbers of patients and are particularly worried about the limited awareness in medical community . CardiacThe pathogenesis of chronic CHD involves a progressive inflammatory process and adverse immune response with myocardial necrosis and damage to the conduction tissue, leading to electrocardiographic changes, such as atrioventricular and intraventricular blocks, sinus node dysfunction, ventricular arrhythmias and sudden cardiac death. The presence of myocardial inflammation, necrosis and fibrosis may result in left ventricular (LV) segmental wall motion abnormalities and congestive heart failure. Derangements in the coronary microcirculation are likely to cause ischemic-like symptoms, electrocardiographic (ECG) abnormalities and perfusion defects .Patients with CHD are classified according to symptoms and presence of myocardial abnormalities. The presence of typical ECG abnormalities usually defines the diagnosis of chronic CHD . The mosChronic CHD carries a worse prognosis when compared to ischemic and other non-ischemic causes of heart failure . The preIdentifying patients with chronic CHD at increased risk of SCD is crucial, as they could benefit from prophylactic implantation of cardioverter-defibrillators ,12,13. EElectrocardiogram (ECG) is the most important exam to characterize in which phase Chagas disease patient is. It is an easy method to perform, widely available worldwide and with high sensitivity. If the ECG remains normal, the prognosis of those patients is similar to the general population. It is important to perform ECG on a serial basis annually to assess possible disease progression. Asymptomatic infected patients with normal ECG (chronic indeterminate form) should be followed annually with clinical evaluation and ECG. In the presence of symptoms and/or ECG abnormalities, patients should be ideally submitted to 24-h Holter, exercise test and echocardiography. Usually, the ECG is the first exam to undergo changes when there is cardiac involvement in the chronic phase of Chagas disease. The presence of typical ECG abnormalities is associated with increased risk of progression to more severe cardiomyopathy.There are some unspecific findings in ECG that need individualized evaluation, as they alone are not sufficient to diagnose cardiac involvement such as: sinus bradycardia, low voltage QRS, incomplete right bundle branch block, anterosuperior hemiblock, first-degree atrioventricular block and unspecific ST-T findings. The most commons early findings are right bundle branch block with or without left anterior fascicular block, second- and third-degree atrioventricular block. Other alterations associated with CHD are complex ventricular arrythmias, atrial fibrillation, complete atrioventricular block and left brunch block. ECG changes associated with worse prognosis are frequent premature ventricular contractions (PVCs), increased QT-interval dispersion, low-voltage QRS, QRS fragmentation, polymorphous or repetitive non-sustained ventricular tachycardia and prolonged QRS.When an electrocardiographic alteration compatible with Chagas’ disease is identified, the patient is reclassified from chronic undetermined benign form to a cardiac form with a poorer prognosis and additional cardiac and gastrointestinal check-up is recommended  6]..6].A 24 h Holter is recommended when available and in patients with symptoms suggestive of cardiac arrhythmias, such as palpitations, presyncope and syncope, or ECG abnormalities like bradyarrhythmia, second degree atrioventricular block and multiple PVCs. Often, brady and tachyarrhythmias are identified in the same patient, and this differential diagnosis is important for indicating a pacemaker implant associated or not with the implantable cardioverter defibrillator (ICD). A 24 h Holter is useful to identify an increased risk of sudden cardiac death and unmask signs of autonomic dysfunction, such as reduced heart rate variability. The presence of non-sustained ventricular tachycardia on the 24 h Holter is one criterion that worsens the prognosis of patients with CHD. Major electrocardiographic changes are sinus node dysfunction, atrioventricular block, or frequent PVCs that becomes more complex and frequent with the disease progression. The presence of ventricular tachycardia is associated with left or global ventricular dysfunction and, when sustained, configures a worse prognosis. The main cause of sudden death in CHD is ventricular fibrillation, which is more frequent when there are previous episodes of ventricular tachycardia, but it can be the first manifestation of the disease or its terminal event in patients with severe ventricular dysfunction and heart failure. CHD is one of the most common indications of artificial pacemaker implants in Brazil, and a 24 h Holter is important to help the clinician to confirm the need of the device, indicate the best type and the follow-up after the implant, as this can detect faulty functioning of the stimulation system or orientate better programming . RegardiWhen available, exercise tests should be performed to understand the responses of Chagas disease patients to hemodynamic stress and to assess the functional capacity. The most important finding to observe on ECG during the exam are ventricular arrhythmias, which are independent predictors of mortality ,15. TheyEchocardiography has become the most common method to assess and follow up patients with CHD. The presence of echocardiographic abnormalities allows us to stage disease progression . In earlThe landmark lesions of CHD are LV apical aneurysms. In order to identify these aneurysms, it is important to use not only standard but also angulated views such as modified four- and two-chambers views, aiming posteriorly and avoiding foreshortening, dropout or near-field artifacts. Aneurysms are not limited to the apex or inferolateral walls, the most common sites, and may be associated to the presence of intraventricular mural thrombi. Right ventricular (RV) aneurysm is uncommon. The prevalence of LV aneurysm is inferior to 10% in asymptomatic patients but has been reported as superior to 50% in patients with more advanced stages, with moderate to severe LV global systolic dysfunction. Symptomatic patients may present regional wall motion abnormalities, LV or biventricular dilatation with diminished LV ejection fraction.Echocardiograms should be performed at least once in every patient with positive serology and can be repeated each 3–5 years or anytime if ECG abnormalities are detected and should follow the European Association of Cardiovascular Imaging/American Society of Echocardiography task force’s recommendations on chamber quantification, LV function and morphology, RV function and valvular analysis .Chamber volumes and global ventricular function should be evaluated by bidimensional (2D) echocardiography through biplane method of disks (Simpson’s) and tridimensional (3D) echocardiography, whenever possible. Tridimensional is more accurate than 2D echo for assessing LV volumes and ejection fraction (EF), particularly in the presence of wall motion abnormalities when there is a distorted LV geometry, as it allows visualization of cardiac chambers without geometric assumptions. It can also avoid foreshortening, being more accurate to detect the presence of aneurysms or thrombus. Regional wall motion abnormalities are most often located in the apex, inferior and inferolateral walls and should be assessed in multiple angles. Evaluation should include valvular structure and function, as functional mitral and tricuspid valve regurgitation are common in advanced cases with ventricular remodeling and valve annular dilation.Strain is a measure of myocardial deformation, defined as the change of length of the myocardium that allows a more precise and quantitative measurement of the regional myocardial function, overcoming the subjective evaluation by conventional echocardiography. Strain obtained by speckle-tracking is the method of choice because it is not angle dependent. Regional strain is of particular interest in CHD due to the frequent segmental myocardial involvement , being pEchocardiography may potentially be used to study ventricular dyssynchrony in CHD ,22. DuarEchocardiography is an inexpensive and readily available method, being very useful to stage and follow these patients, giving hemodynamic information that can be extremely helpful in advanced heart failure. On the other hand, the method is less sensitive to evaluate the presence of fibrosis and is not able to detect inflammation.Cardiac computed tomography (CT) has an excellent negative predictive value to exclude coronary artery disease through coronary computed tomography angiogram (CTA), being extremely useful in patients with low to intermediate pre-test probability. Cardiac CT can also be used to plan electrophysiologic procedures, evaluate LV morphology, including the detection of regional wall motion abnormalities, apical aneurysms and intracardiac thrombi, and to calculate LV function in patients with difficult echocardiographic windows and contraindication to CMR, such as the presence of an implanted cardiac device ,5.CMR has a superior capability for anatomic and functional evaluation of cardiac chambers and measurement of right and left ventricular EF. LV systolic dysfunction is the strongest predictor of morbidity and mortality in CHD, and detection of subclinical dysfunction may orient therapeutic measures that would help in delaying the progression of the disease. Regional wall motion abnormalities, thrombus and aneurysms can be easily recognized .Myocardial fibrosis is a histopathological finding common to several types of cardiovascular diseases and is associated with morbidity and mortality ,24. The The presence of fibrotic myocardial lesions is associated to reentrant circuits, which are the main pathophysiologic mechanism of ventricular tachyarrhythmias. Recent studies reveal that the degree of myocardial fibrosis increases progressively from the mildest to the most severe disease stages and late gadolinium contrast enhancement (LGE) evaluated on CMR is currently the best non-invasive method to assess it, being a marker of subclinical involvement with proven prognostic value ,27,28. TDevelopment of fibrosis in Chagas disease patients predominates in territories of distal circulation, particularly in apical and inferolateral regions, and the pattern of LGE is usually meso-epicardial or transmural , which dNonetheless, LGE fails to account for interstitial and diffuse collagen distribution, which leads to underestimation of the total myocardial fibrosis mass . The capPatients with chronic CHD have an increased risk of SCD compared to other cardiomyopathies. The presence of fibrosis, dysautonomia and persistent cardiac inflammation could contribute to the risk of SCD, offering a substrate for ventricular tachycardia (VT). Molecular imaging with single photon emission computed tomography (SPECT) or positron emission tomography (PET) using a variety of radiotracers are valuable tools to identify changes that predispose to arrhythmia, such as hypoperfusion, inflammation and abnormal sympathetic innervation.Myocardial perfusion imaging may be performed with SPECT or hybrid SPECT-CT equipment, using technetium-99m labeled radiopharmaceuticals such as tetrofosmin or sestamibi , or withIt has been demonstrated that histogram bandwidth and phase-derived standard deviation may be analyzed in gated-SPECT myocardial perfusion imaging , which aAbnormalities in cardiac sympathetic innervation may play a central role in the mechanism triggering serious ventricular arrhythmias and SCD in patients with non-ischemic cardiomyopathy. The work of Miranda  showed tThe presence of persistent cardiac inflammation may also be related to ventricular tachycardia and the risk of sudden death. Persistent subclinical inflammation in areas adjacent to fibrotic regions may act as a trigger for reentry in the presence of fibrosis. In addition, active inflammation may increase the automaticity within inflamed areas. Radionuclide imaging can allow the identification of areas of inflammation of the myocardium in patients with non-ischemic cardiomyopathies .18F-fluorodeoxyglucose (18F-FDG) is a glucose analogue being physiologically captured by cardiomyocytes which can be used to evaluate the pathologic uptake by inflammatory cells. Recently, the use of 18F-FDG PET-CT has been studied in patients with sarcoidosis, demonstrating that the presence of focal perfusion defects and increased FDG uptake in patients with suspected cardiac sarcoidosis identified subjects at higher risk of death or ventricular tachycardia [hycardia .The use of PET-CT in Chagas disease has not yet been systematically studied. There are several similarities between Chagas disease and sarcoidosis, so the use of this imaging technique could potentially be useful in assessing the presence of inflammation and prognosis. Both are associated with changes in the conduction system and complex ventricular arrhythmias and with the presence of meso-epicardial fibrosis.68Ga) labeled-DOTATOC may overcome some limitations of the 18F-FDG, as has been reported for cardiac sarcoidosis and CHD [Currently, patients with chronic Chagas disease are not routinely evaluated for the presence of inflammation. Three case reports have described increased uptake of 18F-FDG PET in patients with Chagas disease and ventricular tachycardia, suggesting that the presence of inflammation could be involved in the genesis of the arrhythmia ,41. Rece and CHD ,43, as iPET-CT has the advantage of a higher spatial resolution when compared to scintigraphy and, unlike CMR, it can be used in patients with implantable cardiac devices. Better understanding of the role of inflammation in these patients may provide novel treatment strategies, such as localization of the anatomic substrate before ablation of VT, and improved risk stratification and orientation about primary prevention with ICD implantation.Unfortunately, despite its significant mortality, there is no clear recommendation for early ICD implantation in patients with CHD in the current guidelines. Ideally, the risk of SCD should be evaluated in earlier stages of the disease. New imaging parameters that are useful to identify factors involved in the genesis of arrhythmia such as fibrosis, inflammation and dysautonomia  can be aFibrosis, inflammation and dysautonomia are involved in the genesis of ventricular arrhythmia in CHD. Due to the risk of sudden death, it is important that such events are early identified, so that SCD preventive measures can be taken. Myocardial fibrotic areas leads to a macro reentry circuit that triggers ventricular tachycardia and CMR is an accurate method to identify these areas. The presence of inflammatory process, detected through PET-CT with FDG or DOTATOC, may be involved in the genesis of the arrhythmia in CHD. Finally, studies of myocardial dysautonomia identified using myocardial SPECT-CT with MIBG have reported an association between denervated areas and ventricular electrical instability, even in the presence of viable myocardium. Echocardiography, despite not being sensitive enough to identify fibrosis and denervation, can indicate severe ventricular dysfunction, which is also associated with an increased risk of sudden death. Other non-invasive tests such as ECG, 24 h Holter and exercise test can identify both dysautonomia, and the presence of ventricular electrical instability, demonstrating an increased risk of sudden death in CHD patients. Thereby, traditional non-invasive diagnostic methods associated to new image parameters obtained through CMR, SPECT-CT and PET-CT can improve risk stratification of SCD and play a promising role in the implementation of primary preventive strategies.


The onset prevention and early diagnosis in cardiotoxicity due to cancer chemotherapy are important, and it is important to detect cardiac dysfunction at an early stage and start treatment to enhance the therapeutic effect.2) and cyclophosphamide followed by docetaxel. Two months after the initiation of her chemotherapy, the left ventricular (LV) ejection fraction (LVEF) determined by echocardiography fell to 41.2%, and she was diagnosed with cancer therapy-related cardiac dysfunction (CTRCD). Three months after the initiation of cancer treatment, the peak velocity of late diastolic transmitral Doppler flow (A wave) became undetectable. Peak longitudinal strain (LS) and peak LS rate, which reflect left atrium (LA) reservoir function, gradually declined like the LVEF and LV-global LS (GLS). Seven months after the initiation of cancer treatment, she was diagnosed with acute decompensated heart failure. The changes in peak LS and peak LS at the onset were greater than those in LVEF and LV-GLS.A 31-year-old female with breast cancer received chemotherapy with epirubicin (400 mg/mThis is a case report suggesting that LA reservoir function might be a more sensitive indicator than LVEF or LV-GLS in detecting CTRCD and that LA booster function might be the earliest. Left atrium reservoir function might be a more sensitive than conventional LV pump function and optimal indicator in CTRCD. Therefore, onset prevention and early diagnosis are important, and regular monitoring is essential during cancer treatment. We have already reported a novel assessment of cancer therapy-related cardiac dysfunction (CTRCD) by cardiac computed tomography.,,Cardiac ultrasonography is the most common method for assessing cardiac function. Left ventricular (LV) ejection fraction (LVEF) is effective when functional myocardial damage becomes apparent, but it does not have sufficient sensitivity and specificity to detect myocardial damage caused by a potential antineoplastic agent at an early stage. It was shown that long-axis myocardial strain [global longitudinal strain (GLS)] by the two-dimensional speckle tracking (2DS) method can be an indicator of potential cardiac dysfunction. Attempts to detect myocardial damage earlier than LVEF by combining with the biomarker troponin have been made.2) and cyclophosphamide  was administered every 3 weeks for four cycles. Then, she was administered docetaxel  every 3 weeks for four cycles.A 31-year-old female patient received a diagnosis of poor-risk breast cancer. She had a smoking habit. She underwent total mastectomy and was indicated for postoperative chemotherapy. Pretreatment transthoracic echocardiography (TTE) revealed a low-normal LV function . Adjuvant combination chemotherapy with epirubicin  and late (A) diastolic transmitral Doppler flow were measured using the apical four-chamber view with the sample volume placed at the tip of the mitral leaflets. We obtained echocardiographic images several ultrasound vendors (frame rate 43–50 Hz) and performed the 2DS tracking echocardiography analysis using TomTec Image-Arena™  software. Speckles were tracked frame by frame throughout the LV myocardium over the course of one cardiac cycle; basal, mid, and apical regions of interest were then created and were manually adjusted whenever needed. Because dedicated software for LAS analysis has not yet been released, we also used this software to study LA deformation. Left atrium strain was measured using strain indices calculated as the average of the three segments  obtained using apical four-chamber views. We used R-wave trigger method. All sonographers were blinded to the patient’s clinical history and data to minimize bias.Figure 1 demonstrates typical measurement examples of the LAS  and LAS rate  evaluated by the 2DS method. The systolic strain  and the A wave became undetectable. This means that the LA booster function has fallen into a ‘loss-of-function’. The lower panels in timeline demonstrate the actual waveform obtained by TTE.No further additional heart failure had occurred at regular medical check-ups.Figure 2, it was suggested that the LA reservoir function might be a more sensitive indicator than LVEF and LV-GLS in detecting CTRCD. Furthermore, as shown in timeline, LA booster function has been lost, and this appears only 3 months after the initiation of anticancer treatment, which might be the earliest indicator. What is most striking is the early increase in LA volume, which reflects LA emptying fraction, noted only 2 months after commencement of chemotherapy and continuing to increase until the onset of ADHF.In this case, as shown in et al.et al.Peak LS and peak LSR have been reported to correlate well with LV end-diastolic pressure (LVEDP),The only limitation of this study was that we were unable to observe intracardiac pressure using cardiac catheterization. It is not realistic to perform frequent catheterizations during anticancer treatment. Therefore, this phenomenon was observed using TTE, which may have been reasonable.This is a case report suggesting that LA reservoir function might be a more sensitive indicator than LVEF or LV-GLS in detecting CTRCD and that LA booster function might be the earliest, although LA pump strain value should be read in light of underlying LA volume.In conclusion, LA reservoir function might be a more sensitive than conventional LV pump function and optimal indicator in CTRCD.Daisuke Sueta is a Lecturer, Department of Cardiovascular Medicine, Kumamoto University Hospital.European Heart Journal - Case Reports online.ytaa355_Supplementary_DataClick here for additional data file.


Ischemic heart disease and its sequelae are one of the major contributors to morbidity and mortality worldwide. Over the last decades, technological developments have strengthened the role of noninvasive imaging for detection, risk stratification, and management of patients with ischemic heart disease. Cardiac magnetic resonance (CMR) imaging incorporates both functional and morphological characterization of the heart to determine presence, acuteness, and severity of ischemic heart disease by evaluating myocardial wall motion and function, the presence and extent of myocardial edema, ischemia, and scarring. Currently established clinical protocols have already demonstrated their diagnostic and prognostic value. Nevertheless, there are emerging imaging technologies that provide additional information based on advanced quantification of imaging biomarkers and improved diagnostic accuracy, therefore potentially allowing reduction or avoidance of contrast and/or stressor agents. The aim of this review is to summarize the current state of the art of CMR imaging for ischemic heart disease and to provide insights into promising future developments. Ischemic heart disease is a major contributor to mortality and morbidity worldwide.Cardiac magnetic resonance (CMR) allows evaluation of regional and global myocardial function.CMR provides superior myocardial characterization, including visualization of edema, infarct, microvascular obstruction, and hemorrhageCurrent CMR imaging strategies for perfusion and viability assessment have widely accepted diagnostic and prognostic value.Emerging imaging techniques aim to improve diagnostic and prognostic power of CMR.Cardiovascular disease remains one of the most common causes of death in industrialized nations  with iscOver the last decade, technological advances have strengthened the role of noninvasive cardiovascular imaging techniques for the detection, quantification, and risk stratification in acute and chronic IHD. Alongside echocardiography, nuclear medicine, and computed tomography, cardiac magnetic resonance (CMR) has evolved as an essential tool for the characterization of IHD , 5. In aA.Functional analysis to evaluate wall motion disturbances and ventricular function;B.Edema imaging to differentiate between acute and chronic myocardial injuries;C.Stress imaging to detect inducible ischemia;D.Infarct imaging to visualize and quantify permanent myocardial injuryIn general, evaluation of IHD with CMR relies on four major pillars that have different roles depending on the progression of the disease:CMR allows for the detection of subclinical IHD (A + C) or clinically evident IHD , and risk stratification in patients suffering from acute or chronic IHD . The aimi.e., dyskinesia. A short period of myocardial ischemia (< 15 min) is able to induce transient ventricular dysfunction , which can be present for hours or even up to days, even in the event of timely restoration of coronary blood flow. In contrast, the term hibernating myocardium describes the effect of a longer lasting or repetitive exposure of the myocardium to an ischemic state. This results in partial or complete myocardial contractile dysfunction, which can be potentially reversed by revascularization. Finally, if myocardial ischemia is too severe or prolonged, myocardial necrosis will lead to irreversible loss of myocardial contractile function [Analysis of myocardial wall motion and ventricular volumes with cine sequences is a basic CMR concept and a widely accepted reference standard for the evaluation of left and right myocardial wall motion and ventricular function . IHD leafunction .The clinical assessment of wall motion is mostly performed on a visual basis that does not allow quantification of wall motion impairment. Changes in wall thickness may serve as a basic tool to measure wall motion abnormalities. However, this method is time-consuming and has not been accepted and implemented widely in the clinical routine . Cine imk-space, transformation of sparsity, and iterative nonlinear reconstruction. Therefore, compressed sensing allows for up to 40-fold acceleration while still providing accurate assessment of LV function [Standard cine imaging requires the collection of image data over several heart beats and results in a “segmented” acquisition of a single cardiac plane, typically using a balanced steady-state free precession (bSSFP) or fast gradient echo technique . Therefofunction .strain imaging has been established. Early applications needed the acquisition of special “tagged” sequences that allow the visualization and quantification of myocardial deformation on CMR images. Alongside further developments, such as “displacement encoding with stimulated echoes and strain-encoded” CMR, the application of feature tracking algorithms on regular cine images helped strain imaging to gain attention in clinical routine [To obtain quantifiable information about wall motion, the concept of  routine . Therefoe.g., for segmenting CMR imaging data [In summary, strain imaging is able to determine myocardial deformation over the cardiac cycle. Cardiac deformation during contraction can be subdivided into three principal motion patterns: longitudinal and circumferential shortening and radial increase of wall thickness. Each motion pattern is related to a different myocardial layer, which allows the derivation of the location and severity of the impairment . Strain ing data .Fig. 1Ti.e., the area affected by the occlusion of a coronary artery [Discrimination between acute and chronic infarcts relies on the capability of CMR to detect myocardial edema. Acute ischemic damage leads to cell death and inflammatory response, which leads to accumulation of water in the affected territory. Such territory is usually referred to as the area-at-risk (AAR), y artery . Within y artery . This iny artery .Conventional T2-weighted images are preferred for the detection of myocardial edema compared with conventional T1-weighted images . In clinAlternatively, the contrast-enhanced cine bSSFP (CE-bSSFP) technique has been investigated to evaluate myocardial edema in myocardial infarction see Fig. . CE-bSSFe.g., modified Look-Locker inversion recovery, MOLLI), shortened MOLLI (ShMOLLI) [e.g., saturation recovery single-shot acquisition) [Over the last years, T1 and T2 mapping techniques have emerged as promising myocardial characterization tools , 40. TheShMOLLI) , 42, satisition) , or the isition) . In clinisition) , T2 effee.g., by turbo spin echo sequences with varying echo times [gradient and spin echo, GRaSE) [T2 mapping is performed by pixel-wise fitting of a T2 decay curve from a series of T2-weighted images. These images can be acquired by different sequence types, ho times , a bSSFPho times , 48, or , GRaSE) . All of e.g., by blood degradation products such as deoxyhemoglobin and methemoglobin induce a decrease in T2 in the infarct core [Myocardial edema will prolong native T1 as well as T2 relaxation times  or a high dose to induce myocardial ischemia in territories with significant coronary stenosis that can be depicted by the onset of wall-motion abnormalities. High-dose dobutamine CMR is superior to dobutamine stress echo in regard to diagnostic accuracy [Second, positive inotropes and chronotropes such as dobutamine can be administered to increase myocardial oxygen demand comparable to physical exercising . Dobutamaccuracy . It has accuracy . Korosogaccuracy  have shoBoth stress techniques, however, have limitations. The administration of vasodilators or inotropes carries the risk of potential life-threatening side effects. Imaging at stress has to be performed at the optimal time point when the stress effect is maximized. Furthermore, conventional adenosine and dobutamine stress images are currently analyzed by semiquantitative methods, limiting the evaluation to visual detection  which also requires the identification of remote tissue to compare pathological changes with . ConsequIrrespective of the accumulating evidence for the value of stress CMR, new developments promise to overcome its current limitations. One major goal is to achieve capability of acquiring fully quantitative perfusion data sets , preferaversus 83%). Schneeweis et al. [For dobutamine stress CMR, strain imaging has been implemented to overcome the limitations of visual analysis when evaluating wall motion abnormalities. Korosoglou et al.  have shos et al.  demonstrs et al. . Finallys et al. .As an alternative, stress imaging without the need for pharmacological agent and/or contrast media administration has moved into the current scientific focus.Exercise CMR using MRI compatible treadmills or mountable bikes is a promising method, when contraindications and intolerable side effects prevent the use of a pharmacological stress agent . SeveralStress T1 mapping is a novel way to perform stress imaging without the need for administering contrast media, as it relies on the capability of native T1 mapping to detect changes in myocardial blood volume. Physiological response to vasodilators leads to an increase in myocardial blood volume. Therefore, T1 maps acquired before and during vasodilator stress show a difference in myocardial T1 due to the increased blood volume in the myocardium . Notablyarterial spin labeling. It relies on the tracing of “labeled” water protons by changing their longitudinal magnetization using selective radiofrequency pulses and compare images with and without the inflow of labeled blood. This technique has been evaluated in various animal models of myocardial ischemia and infarction [Another experimental approach to avoid contrast administration for stress imaging is farction , 83, andfarction . Currentfarction , which lFinally, the combination of blood-oxygen-level-dependent imaging with breathing maneuvers has been assessed for the indirect evaluation of myocardial perfusion . Deoxygeversus healthy myocardium. As gadolinium-based contrast agent causes T1 shortening, diseased myocardium appears bright on T1-weighted images. Typically, conventional inversion recovery gradient-echo sequences are used to acquire LGE images. However, a phase-sensitive inversion recovery (PSIR) technique is also available that reduces the need of precise inversion times and provides more consistent signal and contrast. In addition, “synthetic” LGE images can be retrospectively generated from post-contrast T1 maps and allow LGE image evaluation at any theoretical inversion time [Imaging of necrotic tissue (acute infarct) and scar (chronic infarct) is a hallmark of clinical CMR. However, as infarcts may have a diverse histology depending on severity, presence of hemorrhage and/or microvascular obstruction, and changes over the time from coagulation necrosis to mature scar, imaging characteristics may vary. Infarct imaging is typically done using late gadolinium enhancement (LGE) CMR. The basic principle behind LGE is demonstrating the distribution of gadolinium-based contrast agent that normally accumulates in the extracellular space, but, in case of infarction, it can enter the intracellular space through ruptured cell membranes. The extent of gadolinium accumulation is related to the blood volume, tissue perfusion, size of the extracellular space, and amount of necrotic tissue. The LGE phenomenon is caused by delayed gadolinium washout from the diseased ion time .Accuracy of CMR to detect and quantify infarct size has been validated against histopathology in animal studies . Its excTo date, there is no universally accepted method for LGE quantification. Several techniques have been suggested including manual contouring and semi-automated approaches using signal intensity thresholds of 2 to 6 times the standard deviation of the signal from the normal myocardium, the full-width-at-half-maximum approach, and nonbinary techniques , 99. Mos2-STIR.LGE imaging also provides insights into irreversible damage of the microvascular circulation by visualizing microvascular obstruction (MVO), also known as no-reflow phenomenon, and intramyocardial hemorrhage (IMH). Percutaneous revascularization typically aims to restore epicardial blood flow, but may not improve microvascular perfusion. Insufficient microvascular perfusion affects approximately 50% of STEMI patients and manifests as MVO and subsequent IMH . It has The assessment of the extent of nonviable tissue in IHD has significant prognostic value. A meta-analysis incorporating 2,632 patients from 10 randomized trials found that a 5% increase in infarct size correlates to a 20% increase in rates for heart failure-related hospitalization and all-cause mortality . Furtheri.e., more negative) magnetization level, appearing black in the PSIR image. As the hyperenhanced scar regions have shorter T1 relaxation times compared with the blood pool, they still appear bright in the PSIR image. Validation of this approach has shown promising results across scanners from different vendors on both 1.5-T and 3-T magnets [Despite the promising diagnostic and prognostic implications, there are multiple limitations to the current LGE techniques. Due to the similarity between enhancing infarct and blood pool signals, small subendocardial enhancements can sometimes be missed. To overcome this problem, so-called black-blood or dark-blood LGE sequences have been proposed that allow for the visualization of sufficient tissue contrast while simultaneously suppressing blood pool signal, such as the “flow-independent dark-blood delayed enhancement” , and the magnets . Image ee.g., infiltrative diseases or microscopic fibrosis), as myocardial enhancement has to be evaluated relative to reference normal tissue. Mapping techniques, however, measure intrinsic tissue properties, therefore do not rely on reference tissue, thus are capable of assessing diffuse processes such as inflammation in myocarditis or fibrosis in dilated cardiomyopathy. T1 mapping is sensitive to changes in the composition of cellular and interstitial components such as water, protein, fat, and fibrotic tissue. This combination limits the use of native T1 mapping to detect and quantify the extent of myocardial infarct, as edema and infarct may both lead to similar changes in T1 [Another general limitation of LGE imaging is that diffuse myocardial involvement is difficult to quantify . Therefore, novel quantitative techniques, such as relaxation mapping, strain imaging, and quantitative perfusion are emerging and en route to being integrated into clinical workflow and have the potential to improve diagnostic and prognostic performance of CMR in the future. Potential future applications including machine-learning approaches, use of physiologic stressors, and/or the use of molecular imaging in combination with CMR have to be translated from experimental approaches to clinical applications in the future.


Cardiovascular disease (CVD) is the most common cause of mortality in pediatric chronic kidney disease (CKD) patients. Left ventricular (LV) hypertrophy (LVH) is associated with LV diastolic dysfunction (LVDD) development and is used as an early marker of CVD in pediatric CKD. This study aimed to assess the prevalence and risk factors of LVDD and the association between LVH and LVDD in Korean pediatric CKD patients.2.7 and LV-wall thickness z-score > 1.64. LVDD was defined as a mitral peak velocity of early filling to early diastolic mitral annular velocity (E/E’) > 14. Univariate and multivariate logistic regression analyses were performed to evaluate risk factors of LVDD.Data were collected using the baseline data of the Korean cohort study for outcome in patients with pediatric chronic kidney disease, a nationwide, 10-year, prospective, observational cohort study of pediatric CKD. A total of 244 patients were included in the final analysis. Two-dimensional echocardiography and tissue Doppler images were used to evaluate LVH and LVDD. LVH was defined as an LV mass index (LVMI) ≥38 g/m2, and no patients received renal replacement therapy. The mean value of LVMI and E/E’ was 37.0 g/m2.7 and 7.4, respectively. The prevalence of LVH was 40.1 and 17.4% by LVMI ≥38 g/m2.7 and LV-wall thickness z-score, respectively. The prevalence of LVDD was 4.5%, and patients with LVH showed greater risk of LVDD . In the univariate analysis, young age, low hemoglobin level, higher LVMI, and higher LV-wall thickness z-score were associated with LVDD. In the multivariate analysis, young age, low hemoglobin level, and higher LV-wall thickness z-score were independently associated with LVDD.In this study, the male-to-female ratio was 2.2 (168:76) and median age was 11.2 years. The average estimated glomerular filtration rate was 57.4 ml/min/1.73 mThis study shows that LVH patients have a greater risk of LVDD and that anemia is the only modifiable risk factor for LVDD in Korean pediatric CKD patients. Chronic kidney disease (CKD) is an increasing public health issue, and the prevalence of CKD in adults is estimated to be 13.4% worldwide . Life ex2.7 (m2.7) and the LV-wall thickness z-score were used to define LVH with cut-off values of ≥ 38 g/m2.7 and > 1.64 for LVMI and z-score, respectively [In CKD patients, left ventricular (LV) geometry and diastolic function are changed at early stages while systolic functions are preserved until the late stage. These changes are represented as LV hypertrophy (LVH) and diastolic dysfunction (LVDD) by echocardiography and used as an early marker of CVD , 10. Howectively –13. LVDDectively –16. Howez-score to define LVDD in pediatric CKD patients.The aim of this study is to detect the prevalence of LVDD in Korean pediatric CKD and the clinical difference according to the presence of LVDD. In addition, as there is no gold standard method for defining LVDD, we are suggesting a cut-off value of E/E’ normalized to the age-independent We used the baseline data of the KoreaN cohort study for Outcome in patients With Pediatric Chronic Kidney Disease (KNOW-Ped CKD), a nationwide, 10-year, prospective, observational cohort study of pediatric CKD. The design and methods of KNOW-Ped CKD are published . The stuAll the data were obtained in accordance with the ethical principles for medical research involving human subjects established in the Declaration of Helsinki 1975 (revised in 2000).Demographic data and laboratory values were obtained from the web-based data management system, PhactaX (version 1.0). Biochemical values were measured at the hospital laboratories of participating centers. Estimated glomerular filtration rate (eGFR) was calculated using the modified Schwartz equation . The CKD2.7 (LVH 1) or a height-specific normalized LV wall thickness z-score > 1.64 (LVH 2). Early diastolic velocity ratio (E/E’) was evaluated by measuring early mitral valve ventricular filling velocity (E) in conventional echocardiography and early diastolic annular velocity (E’) in tissue Doppler echocardiography. The LVDD was defined using an E/E′ > 14 by tissue Doppler imaging. The E/E’ ratio was normalized to patient age by z-score calculation using a published reference based on 325 healthy children [The hypertension was defined when systolic or diastolic blood pressure was above age-, sex-, and height-specific 95th percentile or when the patient was on anti-hypertensive medication. Two-dimensional echocardiography and tissue Doppler were performed by pediatric cardiologists at each center to measure cardiac parameters according to the American Society of Echocardiography pediatric guidelines . The lefchildren .P < 0.1 from univariate analysis were entered in multivariate regression analysis. A chi-squared test and Fisher’s exact test were used for categorical data. The Youden’s index analyzed by empirical method was used to determine the cut-off value for LVDD by E/E’ z-score as it showed normal distribution.Statistical analysis was conducted by SPSS Version 25. The continuous variables with normal distribution are described as the mean ± standard deviation. The continuous variable with non-normal distribution are expressed as mean ± standard deviation, or median value with interquartile range, whichever describes the data well. A Student’s t-test was used for normally distributed numerical data and Mann–Whitney test was used for non-normally distributed numerical data. Logistic regression analysis was used to evaluate the odds ratio (OR) and confidence interval (CI) for the presence of LVDD associated with each variable. Variable with n = 28; 3 medications, n = 7). Angiotensin-converting-enzyme inhibitors (ACE inhibitors) or angiotensin II receptor blockers (ARBs) were taken in 137 (97.2%) patients and other medications were taken in 4 patients (2.8%). LVMI data showed a mean value of 37.0 g/m2.7 (LVMI/height2.7) and mean LV wall thickness z-score of -2.9. The prevalence of LVH was 40.1% based on LVMI ≥ 38 g/m2.7 and 17.4% based on LV wall thickness z-score > 1.68. Measured for LVDD evaluation, the mean value of E/E’ ratio and E/E’ z-score was 7.4 and 1.3, respectively. The prevalence of LVDD was 4.5% based on E/E’ ratio > 14.Demographic and clinical data for 244 patients are listed in Table To estimate the optimal E/E’ ratio reflecting LVDD in children, we normalized the E/E’ ratio to patient age by calculating the z-score based on published reference data from a cohort of 325 healthy children. Based on the definition of LVDD with a measured E/E’ ratio above 14, the E/E’ z-score optimal cut-off value was estimated by Youden’s index to be 3.415 for predicting LVDD   than those without LVDD. The values of LVMI and LV wall thickness z-score were higher in CKD patients with LVDD (p = 0.002 and p = 0.008) compared with those without LVDD. There were no differences in the levels of serum calcium, serum phosphorus, and calcium x phosphorus product and hypertension prevalence between groups.The comparisons between groups with or without LVDD based on an E/E’ ratio > 14 is shown in Table p = 0.046), low hemoglobin level (p = 0.018), increased LVMI/height2.7 (p = 0.006), and increased LV-wall thickness z-sore (p = 0.011) by univariate logistic regression. However, there was no association between LVDD and hypertension. Even though the prevalence of LVH was not exact according to the different methods of definition, patients with LVDD showed greater risk of LVH .LVDD, defined by measured value of E/E’ > 14, was associated with younger age , presence of LVH2 , and not with age by univariate logistic analysis. Only presence of LVH2 showed association with LVDD in multivariable logistic regression  (Table LVDD, defined by newly suggested E/E’ z-score > 3.415, was associated with increased LV-wall thickness z-sore (OR 1.2, The LVH is a well-known LV geometry change in pediatric CKD patients, which progress as CKD stage advance and showed association with hyperparathyroidism, vitamin D deficiency, anemia, and hypertension in previous studies , 23. PreThe cut-off value of the E/E’ ratio to define LVDD may have influenced the prevalence in our study. There were several studies in which CKD children have worse LVDD than healthy children, and LVDD worsened as CKD progressed , 32. How2.7 and LV wall thickness z-score > 1.64 shows poor concordance and this discrepancy needs to be studied in future research [This study describes the clinical differences associated with the presence of LVDD in pediatric CKD patients. In previous studies, the E/E’ ratio in pediatric CKD showed an association with young age, serum phosphorus level, calcium x phosphorous product, LVMI, and anemia but not with hypertension , 30, 32.research .This study has several limitations. First, echocardiography was performed by pediatric cardiologists in each center without central reading validation, which can show poor concordance between examiners. Second, this study only included data from baseline pre-dialysis CKD patients. Although LVDD may exist in early CKD, it is well known that LVDD worsens as CKD progresses, and a longitudinal study is necessary to evaluate the overall prevalence. Third, the normalized E/E’ z-score was based on a reference from 325 healthy children in the USA. This study includes Korean children, and ethnic differences may influence the results.This study showed a 4.5–10.7% prevalence of LVDD in pre-dialysis CKD, which is associated with young age, anemia, and LV-wall thickness z-score. Further, we suggest an E/E’ z-score of 3.415 as optimal cut-off value to define LVDD in pediatric CKD patients.