The SLC and CSC were compared using a mock circulation loop to assess their capacity to increase cardiac output during mild exercise while avoiding ventricular suction (marked by a negative PLVEDm) and maintaining circulatory stability during blood loss and severe reductions in left ventricular contractility (LVC). The root mean squared hemodynamic deviation (RMSHD) metric was used to assess the clinical acceptability of each controller based on pre-defined hemodynamic limits. We also compared the in-silico results from our previously published paper with our in-vitro outcomes. In the exercise simulation, the SLC increased m of 2.7 mmHg compared to -0.1 mmHg for CSC. A transition to reduced LVC resulted in decreased mean arterial pressure (MAP) and In-vitro and in-silico results demonstrated similar trends to the simulated changes in patient state however the magnitude of hemodynamic changes were different, thus justifying the progression to in-vitro evaluation.Due to a shortage of donor hearts, rotary left ventricular assist devices (LVADs) are used to provide mechanical circulatory support. To address the preload insensitivity of the constant speed controller (CSC) used in conventional LVADs, we developed a preload-based Starling-like controller (SLC). The SLC emulates the Starling law of the heart to maintain mean pump flow ( As patients implanted with rotary left ventricular assist devices (LVADs) progress through different activity levels throughout the day, under-pumping or over-pumping may occur which can lead to pulmonary congestion, impairment of right heart function and collapse of the left ventricle (LV) . Due to Starling and Visscher  demonstrRecently, our group proposed a preload-based Starling-like controller (SLC) that could imitate the native heart’s preload sensitivity . The relFor any newly proposed physiological control system, there is a hierarchy of studies that can be performed to evaluate its efficacy, each having its own advantages and disadvantages. While numerical models are commonly used as the first step during controller evaluation due to the simplicity of model set-up and high reproducibility in results, it is difficult to model the rotary blood pump dynamics accurately due to its complexity. As a result, simulation results involving transient changes of pump speed to a particular perturbation or control action as well as pump flow or speed pulsatility are less reliable. Evaluation of the control techniques in a mock circulation loop (MCL) allows for real world use of an actual pump and therefore a more accurate representation of the pump speed response to simulated changes in patient state. Additionally, flow and pressure sensors can be used as feedback to the controller, which is a more realistic situation than would be obtained using a numerical model. As the steady-state response of the SLC system has only been evaluated in-silico, further assessment using a more advanced bench top apparatus is required to observe the dynamic effects of the pump and other circulatory compartments with this control method. It is therefore of interest to enhance our previous numerical evaluation of the SLC by comparing the SLC system with the clinically used CSC in a validated MCL. In this work, both the temporal and steady state responses of the SLC to three different test scenarios, including moderate exercise, blood-loss and a major reduction in LVC, was assessed and compared with CSC.3) similar to that of blood at 37°C.A physical MCL  includinA VentrAssist LVAD  was used to support the simulated failing heart in the MCL. The LVAD was cannulated with inflow connected to the LV and outflow to the aorta. The left and right atrial, left and right ventricular, systemic arterial, pulmonary arterial and LVAD inlet/outlet pressures were measured using silicone-based transducers . Systemic and pulmonary flow rates were recorded using magnetic flow meters  while LVAD flow rate was monitored by an ultrasonic flowmeter . All data were sampled at 2 KHz and recorded using a dSPACE 1103 . The MCL operational and control software were developed in MATLAB/SIMULINK .m) [m. In cases when the lower preload sensitivity at high flows (compared with linear preload control) turned out to be insufficient for any given patient, the preload sensitivity of the curve as a whole can be increased. A scaling factor (K) was added to provide a means of altering the pump sensitivity to changes in PLVEDm, which makes m represents the mean LV end-diastolic pressure. As the heart beat timing was managed by the automatic MCL controller, the time of PLVED could be precisely determined. By sampling the LV pressure at this moment, PLVED was acquired. The measured PLVED was then passed through a low pass digital filter of 0.25 Hz to smooth the variation and acquire the mean PLVED.The immediate response of the SLC was formulated as a sigmoid relationship between LV stroke work and mean PLVED (PLVEDm)  to emulam) . This liAny change in state  caused aPump speed was measured based on the back electromotive force of the VentrAssist motor coils. A proportional—integral—derivative (PID) controller was developed to track the desired pump flow, P, KI and KD were set to 130 rpm.min/L, 162.5 rpm.min/L/s, and 58.5 rpm.s.min/L, respectively, which provided settling and response times of 2.0 s and 4.5 s, with no overshoot.The PID gains were tuned based on Ziegler–Nichols method  to achiePump speed Both CSC and SLC were subjected to the same assessment protocol. The scaling factor (K) was set to 1.0 for the SLC, while the corresponding speed of the CSC was set to 2100 rpm. Each experiment started with a baseline LV failure condition at rest for 120 s to allow the system to settle prior to performing a step change to one of the three test scenarios . Upon transitioning to the new states, the experiments were continued for another 120 s to achieve the post-transition steady state.max of 1040 to 1880 mmHg/s[-5 and from 110 to 40 dyne.s.cm-5 respectively.To simulate an exercise scenario, 700 mL of fluid was shifted from the systemic venous compliance (SVC) chamber into the circulation, emulating the action of the muscle pump in increasing venous return. Heart rate was increased from 60 to 90 bpm, while LVC was increased from a dP/dt80 mmHg/s. Systemi-5 and from 110 to 210 dyne.s.cm-5 respectively, to simulate vasoconstriction.To simulate blood loss, 300 mL fluid was shifted from the circulation into the systemic venous compliance chamber to emulate blood flowing into the legs. SVR and PVR were increased from 1300 to 1635 dyne.s.cmA major reduction in LVC was simulated by eliminating the LV contractility using the LV electro-pneumatic regulators. For all simulations, the change of parameters was immediate and simultaneous; however, the fluid shifts were completed over a longer duration (but no more than 20 seconds) due to the MCL dynamics. In this MCL, fluid shifts from the SVC to the heart and vice versa were controlled by adjusting the air pressure in the SVC chamber using a manual ball valve. The key MCL parameters used to mimic baseline, exercise, blood-loss, and reduced LVC conditions are listed in The performance of SLC and CSC was compared by observing the changes in l limits , that dex stand for any of the three previously mentioned hemodynamic variables ) of yx(t) outside of LLx and ULx is calculated as follows:To calculate RMSHD, let yx:Finally, RMSHD is calculated as SA) and a rise in pump flow (QP) despite an increase in heart rate with both controllers  compared to CSC (15.1 mmHg) during exercise, which also indicates reduced load on the LV. Moreover, the value of RMSHD for the SLC was 12.7%, less than the half of the value achieved when utilizing CSC (RMSH of 26.4%), indicating a significantly better clinical performance for the SLC.QP¯ . This wain-vitro and in-silico results (in-vitro testing (9.1%), which resulted in higher in-vitro to similar levels (by 5.4% and 5.8% respectively) with SLC, indicating a reduction in ventricular work with SLC. MAP changes were higher in-vitro for both CSC and SLC (6.7% and 7.9% increase respectively) when compared to the numerical model (1.9% decrease with CSC and 1% increase with SLC).When comparing  results , it was m of -0.1 mmHg, indicating LV suction , which subsequently reduced LV preload when compared to CSC.Similar to the previous experiments the CSC and SLC exhibited similar responses to a transition from baseline to LVC reduction when comparing in-silico and  results . The SLCTo date, various physiologically responsive controllers have been proposed for LVAD support  to caterA Starling-like LVAD control method was developed by Stevens et al.  in 2011,Compared to CSC, the SLC evaluated in this study was able to synchronize systemic and pulmonary flow rates irrespective of variations in venous return by emulating the Starling mechanism of the native heart. The SLC produced a lower PLVED than CSC during exercise and reduced LV contractility scenarios, thus potentially providing improved ventricular unloading. Meanwhile, there is evidence that LV suction under CSC may cause a significant reduction in right ventricular performance through endocardial damage and septal shift , 25. ImpWhen simulating a major reduction in LVC, we observed increased preload with CSC whilst MAP dropped. The SLC responded to such rise in preload by increasing the pump speed and flow, which subsequently returned the preload to its previous value. The results showed little benefit of the SLC over constant speed mode, evident by zero RMSHD value for the both methods. Under the SLC, both in-vitro testing [in-vitro results showed similar trends during changes in patient state, there were differences in the magnitude of changes, which could be attributed to differences in simulated patient hemodynamics, starting pump speeds, the lack of a baroreflex in-vitro, and the real-world use of a pump and sensors in-vitro. Providing an exact replica between both simulation platforms is difficult, and the focus of this evaluation paper was to demonstrate the feasibility of our SLC to prevent adverse events under various simulated patient states in an MCL. A full comparison between the two testing benchtops, although interesting, is beyond the scope of this in-vitro physiological control work.Results in the present study clearly established similar trends between in-silico and  testing , with th testing . AlthougAlthough this study focused on using a single preload control line, a full controller should be capable of adapting to variations in the left ventricle (LV) function by automatically adjusting the scaling factor. The process of adapting curves and changing the scaling factor was initially introduced by Salamonsen et al (2012) and Gaddin-vitro study clearly established the superiority of the preload-based SLC over CSC while transitioning from the baseline state to exercise, blood loss, and a major reduction in LVC. The SLC was able to provide a greater pump flow and cardiac output during exercise as compared to the conventional CSC, with less loading on the heart. In addition, it maintained a better safety margin against LV suction during blood loss. Although the CSC maintained suitable hemodynamics during a reduction in LVC, the SLC maintained almost perfect hemodynamic stability. The SLC has the potential to improve patient outcomes substantially through improved cardiac preservation and increased responsiveness to the patient’s requirements in the multiple physiological conditions faced by the LVAD patient—both in hospital and at home.Our


The objectives were to assess the left ventricular (LV) structure and function in regularly trained young athletes, using 2 D conventional echocardiographic (echo) methods and speckle tracking echocardiography (STE). An observational cross-sectional study.Thirty-three footballers and 20 healthy untrained subjects were included in the study. The systolic and diastolic LV functions were evaluated by 2D conventional echo parameters, Doppler method and STE.2) and the LV Mass index (LVMi 97.93±15.58 g/m2) were significantly higher in young athletes as compared with controls. There was no difference regarding the LV systolic function assessed by conventional echo parameters in the 2 study groups. Regarding the diastolic function, the transmitral inflow velocities ratio was significantly higher in athletes  but there was no difference in the filling pressure in the 2 groups. The STE demonstrated a different pattern of LV deformation in the different groups. A significant lower LV global longitudinal strain  and higher radial and circumferential strains have been found in the young athletes as compared with controls. A significant relationship between the GLS values and LVED  and LVMi was also reported in athletes.All the found values were within the normal range. The LV End Diastolic Diameter (LVED 37.24±2.08 mm/mWhile conventional morphological and functional echocardiographic parameters failed to distinguish the adaptations in the athlete’s heart, deformation parameters showed a different pattern of LV mechanics in young footballers versus controls. Athlete's heart is defined by all cardiac adaptations to intense physical exercise , 2. Now,A group of 33 young football players and 20 young untrained controls were enrolled. All the subjects were males. The athletes were selected among those who exercised = 6 hours/week on average for 3 years. Controls were selected among healthy individuals with sedentary lifestyle not involved in any sportive activities. None of the subjects had relevant findings as determined with physical examinations and medical history. All athletes were on a regular intensive exercise program. The study was approved by local Ethics Committee of Hedi Chaker university hospital of Sfax in Tunisia and oral informed consent was obtained before the participation to the protocol. For all the subjects (under 18 years old of age), oral parental consent was also obtained. After physical examination, different parameters were recorded for all participants: height, weight, heart rate and blood pressure. Body surface area (BSA) was calculated by the Mosteller formula . The 2D 2 (LVMi) was obtained from Devereux procedure [For each subject included in the study, the echocardiographic measurements were performed at the left lateral position. The parasternal long-axis view was used for the M-Mode measurements of left atrial diameter (LAD), interventricularseptal, LV posterior wall thickness (IVST and LVPWT), LV end-diastolic and end-systolic dimensions (LVEDd and LVESd). In addition, the left atrial area and volume were determined. The LV fractional shortening (LVFS) was calculated as (LVEDd – LVESd)/LVEDd. The LV ejection fraction (LVEFs) was calculated from LV volumes by the modified biplane Simpson rule and expressed as a percentage.The evaluation of LV Mass Index g/mrocedure . The pulThe following six views were displayed: the apical four-chamber view, the apical three-chamber view, the apical two-chamber view and the three short-axis views, the apex of the LV, the midlevel of the LV, and the basal level of the LV. After tracing endocardial border at an endsystolicframe, the operator could validate the tracking quality and adjust the endocardial border or modify the width of the region of interest. Aortic valve opening and closure were selected on pulsed wave Doppler tracings recorded from the LV outflow tract. Frame rate ranged from 60 to 100 frame/s, and three cardiac cycles were stored in cineloop format for offline analysis. Global longitudinal LV strain (GLS) was defined as the average of negative longitudinal strains of 17 segments of the LV walls in the apical chamber views. Average LV radial and circumferential strain (GRS and GCS) was determined in the short-axis views.Statistical analysis was performed using Statistical Package for Social Sciences version 20.0 . Continuous variables with normal distribution were presented as the mean . Qualitative variables were given as percent. Correlations between continuous variables were assessed using Pearson’s or Spearman’s correlation analysis. Two-way ANOVA with post-hoc analysis to compare the groups was used. A p-value under 0.05 was considered as statistically significant.2), and systolic and diastolic blood pressures  (mmHg)(p> 0.05)  . LVED, LVES, and LA diameters were significantly larger in the athletes group compared with the controls . IVST was significantly higher in the athletes compared with the control group (P = 0.02). Similarly, LVM index was significantly higher in the young football players than in the control group (P = 0.01)  and the E/A ratio was significantly higher in athletes (p< 0.001). Comparison of TDI parameters measured from the lateral mitral annulus also demonstrated similar S’ and E’ rates for all 2 groups  .In this study, the LV longitudinal apical two, three and four-chamber strain and the LV GLS were significantly lower in the athletes as compared with controls , whereas radial and circumferential strains were higher . The seg2, the LV ED diameter was 37.24±2.08 mm/m2 and LVMi was 97.93±15.58 g/m2.As reported in the literature, all these data were significantly higher in the young football players compared to the control group. In our study, the LV systolic function assessed by LVFS and LV EF was similar in the young footballers and the controls. Previous evaluations using this approach have demonstrated similar systolic functions between athletes and sedentary individuals [Athletes develop different cardiac adaptations depending on the exercise program they use. The term “athlete’s heart” is used to describe the characteristic enlargement and hypertrophy of the myocardium in response to repeated exercise stimuli. To compensate the elevated cardiac output, the LV increases the internal diameters and secondary the LV wall thickness, cardiac pressure and heart rate . Aerobicividuals . In someividuals .To highlight the young trained athletes’ heart, previous studies reported the effect of training on diastolic function in these children by using conventional Doppler examination of mitral flow patterns –19. In tAlthough we identified similar LV systolic function conventionally , different supplementary methods may be needed to evaluate intrinsic myocardial functions in athletes with different LV geometry and diameters. So, more recent studies focused on the speckle tracking imaging for the assessment of the LV global and regional function. The STE or strain analysis is a relatively new and non-invasive imaging method based on tracking of characteristic speckle patterns created by interference of ultrasound beams in the myocardium, and has the advantage of measuring tissue velocities and deformation in an angle-independent fashion. The technique allows for simultaneous qualification in the long and short axes and quantification of regional wall motion abnormalities in all the myocardial segments . Before A limitation for our study was the relatively low case number of each group. The whole study population was consisted of male subjects. However, a previous study has demonstrated no gender-associated differences in strain imaging . We usedThis study evaluated LV systolic and diastolic functions in young athletes using conventional echocardiographic parameters and speckle tracking imaging method. Conventional echocardiography can detect some differences in trained young athletes’ heart but it fails to reveal differences in intrinsic myocardial functions. Speckle tracking echocardiography showed a different pattern of LV deformation in athletes versus untrained healthy subjects. Longitudinalstrain was lower in young athletes as compared with controls, whileradial and circumferential strains werehigher in athletes. Speckle tracking analysis canbe useful for identifying previously undetected differencesregarding the young athlete’s heart.The athlete's heart is defined by all cardiac adaptations to intense physical exercise. The development of two-dimensional echocardiography led to important further advances to understand the cardiac modifications. Recently, novel echocardiographic techniques such as speckle tracking echocardiography provided further insights into the morphological and functional myocardial properties.The speckle tracking echocardiography is a relatively new non-invasive imaging technique that allows an objective assessment of the regional and global myocardial function.Most of the previous relevant studies in the literature included adults with very limited data concerning young athletes. The present study highlights the importance of the echocardiographic study to detect progressive adaptations in the young athletes’ heart to regular sport activity and training.The conventional echocardiography can detect some differences in young athletes’ heart but it is incapable to reveal differences in intrinsic myocardial functions. Thereby, the evaluation of speckle tracking echocardiography can be useful for identifying previously undetected differences regarding athlete’s heart. The present study showed a lower left ventricular longitudinal strain in young athletes as compared with controls, while radial and circumferential strains were higher in athletes.Considering our results and the large heterogeneity of echocardiographic pattern generally found in adolescent subjects, several possible clinical applications of deformation parameters approach can be advised.


Children with chronic kidney disease (CKD) have increased cardiovascular mortality. Identifying high-risk children who may benefit from further therapeutic intervention is difficult as cardiovascular abnormalities are subtle. Although transthoracic echocardiography may be used to detect sub-clinical abnormalities, it has well-known problems with reproducibility that limit its ability to accurately detect these changes. Cardiovascular magnetic resonance (CMR) is the reference standard method for assessing blood flow, cardiac structure and function. Furthermore, recent innovations enable the assessment of radial and longitudinal myocardial velocity, such that detection of sub-clinical changes is now possible. Thus, CMR may be ideal for cardiovascular assessment in pediatric CKD. This study aims to comprehensively assess cardiovascular function in pediatric CKD using CMR and determine its relationship with CKD severity.A total of 120 children  underwent CMR with non-invasive blood pressure (BP) measurements. Cardiovascular parameters measured included systemic vascular resistance (SVR), total arterial compliance (TAC), left ventricular (LV) structure, ejection fraction (EF), cardiac timings, radial and longitudinal systolic and diastolic myocardial velocities. Between group comparisons and regression modelling were used to identify abnormalities in CKD and determine the effects of renal severity on myocardial function.The elevation in mean BP in CKD was accompanied by significantly increased afterload (SVR), without evidence of arterial stiffness (TAC) or increased fluid overload. Left ventricular volumes and global function were not abnormal in CKD. However, there was evidence of LV remodelling, prolongation of isovolumic relaxation time and reduced systolic and diastolic myocardial velocities.Abnormal cardiovascular function is evident in pre-dialysis pediatric CKD. Novel CMR biomarkers may be useful for the detection of subtle abnormalities in this population. Further studies are needed to determine to prognostic value of these biomarkers.The online version of this article (10.1186/s12968-018-0444-0) contains supplementary material, which is available to authorized users. Cardiovascular events are a leading cause of death in pediatric chronic kidney disease  (CKD). TCardiovascular magnetic resonance (CMR) cine imaging is the reference standard method of assessing LV volumes, ejection fraction (EF) and mass . Novel CThe objectives of this study were to i) evaluate any differences in vascular and cardiac phenotype between healthy children and those with CKD, ii) determine the relationship between vascular and cardiac phenotype and any additional effect of CKD, iii) assess the relationship between markers of renal disease and cardiovascular phenotype.p < 0.05) to detect a difference of 3 mmHg in MBP  and 20 healthy volunteers. The CKD patients were divided into 3 groups based on CKD stage: Mild (CKD stage 1–2), Moderate (CKD stage 3) and Severe (CKD stage 4–5). The study was powered to detect differences in mean arterial BP (MBP) between the groups . For between group comparisons, a sample size of 14 children per group provided 90% power  age < 7 or > 18 years, ii) congenital structural heart disease or primary myocardial disease, iii) primary renovascular disease, iv) active vasculitis v) cardiac arrhythmia, vi) medical devices precluding CMR, vii) history of current or previous renal replacement therapy and viii) acutely deteriorating renal function. This study was approved by UK national research ethics service . Informed parental consent and patient assent was obtained from all participants.All CKD participants had blood and urine tests as part of their outpatient care including: haemoglobin (Hb), urea, creatinine, electrolytes, calcium, phosphate, intact parathyroid hormone level (PTH), and urine albumin to creatinine ratio measurements. The eGFR was estimated by modified Schwartz formula. Neither blood nor urine tests were performed for healthy controls.Imaging was performed on a 1.5 T CMR system  with vector cardiographic gating. All CMR images were processed using in-house plug-ins developed for open-source DICOM software OsiriX   [Epicardial LV borders were manually traced in end-diastole and combined with endocardial borders to obtain LV mass (LVM). The effect of body size on LV mass was controlled by both indexing to height to the power of 2.7 (LVMht2.7)  and divi2.7) .The right atrial and left atrial areas were measured in diastole from 4-chamber view (using the same sequence) and indexed to BSA.LV outflow tract and mitral inflow velocities were assessed with a free-breathing high temporal resolution real-time UNFOLD-SENSE spiral PCMR sequence. This sequence has previously been validated against Doppler echocardiography . Scan paThe mitral valve orifice and LV outflow tract were manually segmented from the resultant inflow and outflow curves to obtain the isovolumic relaxation time (IRT), isovolumic contraction time (ICT) and ejection time (ET) as previously described . MyocardLV myocardial velocities was measured using a free breathing self-navigated golden-angle spiral TPM sequence planned in the mid LV short axis view , 15. ScaAll TPM indices were measured from a mid LV short axis slice. Each acquisition produces a magnitude image and 3 phase images . The epi- and endocardial borders were manually segmented on the magnitude image for all frames and regions of interest were transferred to the accompanying phase images. From these masked phase images, radial velocity was calculated by transforming the x and y-direction velocities to an internal polar coordinate system using the LV center of mass as a reference point , 15. TheAortic flow assessment was performed using a breath held retrospectively-gated, spiral SENSE PCMR just above the sinotubular junction . Scan paThe aorta was segmented using a semi-automatic vessel edge detection algorithm with manual operator correction. The SV was derived from the flow curve and multiplied by heart rate to calculate cardiac output (CO). The maximum (AoMax) and minimum (AoMin) cross-sectional areas of the ascending aorta over the cardiac cycle were also recorded.Brachial systolic, diastolic and mean arterial BPs  were measured using a CMR compatible oscillometric sphygmomanometer  during CMR image acquisition. This enabled optimum combination of BP and flow data for calculation of vascular indices. All BP measurements were acquired with an appropriate sized arm cuff after the subject had been lying in the scanner for at least 10 min. Pulse pressure (PP) was the difference between SBP and DBP.Total systemic vascular resistance (SVR) was calculated by dividing MBP by cardiac output (CO) . Total ap-values are listed in the respective tables. Post-hoc pairwise comparison was performed on parameters significantly different on ANOVA testing. The Bonferroni method was used to adjust for potential Type 1 errors in the pairwise comparisons. Spearman’s correlation coefficient (rho) was used to determine the relationship between specific vascular and cardiac phenotypic markers (objective 2) that were significant on ANOVA testing. Multi-variable ANOVA models were also constructed to examine the independent effect of CKD group. Spearman’s correlation coefficient was also used to determine the relationship between markers of renal disease severity - eGFR, hemoglobin (Hb) and PTH and significant abnormal cardiac and vascular indices - MVR, IRT, S′, E’, MBP, SVR (objective 3). Multi-variable linear regression was used to determine the independent effect of renal severity on cardiac markers by controlling for vascular phenotype. Only patients with recent blood tests were included into models involving blood indices. A p value < 0.05 was considered statistically significant, except where Bonferroni correction was applied as indicated. Indices not statistically different to healthy subjects have been described as ‘normal’.Statistical analyses were performed using Stata 13 . Data were examined for normality using Shapiro-Wilk test and non-normally distributed data was transformed using a zero-skewness log transform prior to analysis. Descriptive statistics were expressed as mean (± standard deviation) or geometric mean (± geometric standard deviation) if data was log transformed. Between CKD group differences in vascular and cardiac phenotype were assessed using analysis of variance (ANOVA) (objective 1). Levene’s test was used to assess for homogeneity of variances across the groups and Welch’s correction was applied for non-homogeneous variance. Six groups of statistical tests comparing healthy controls to patients were performed in the following domains - baseline characteristics, blood pressure, vascular phenotype, global cardiac structure and function, cardiac timings and mitral velocities, and tissue phase mapping. Each group of tests was considered a single family of statistical inferences and the family-wise error rate was controlled using Bonferroni correction. The corresponding corrected critical n = 100) consisted of 40 children with mild CKD (stage 1–2: eGFR 78.6 ± 8.8 ml/min/1.73 m2), 40 children with moderate CKD (stage 3: eGFR 48.3 ± 8.4 ml/min/1.73 m2) and 20 children with severe CKD (eGFR 19.2 ± 6.5 ml/min/1.73 m2). Twenty-five (25%) children  had a prior diagnosis of hypertension and were on treatment  and renal dysplasia . All other causes represented < 10% of the population. Eight CKD children had undergone a previous nephrectomy. No children had previously received or were currently receiving renal replacement therapy as per exclusion criteria. None of the healthy subjects (n = 20) had any significant past medical history nor were they taking any medications. There were no differences in age, BSA or sex distribution between groups (Table p < 0.03). The severe CKD group also had highest parathyroid hormone (PTH) (p = 0.01). There was no difference in Hb between the groups (p = 0.57). Outline of blood and urine tests results of study population can be seen in Additional file The CKD cohort n = 00 consisp < 0.001, Table p < 0.05) on pairwise comparison. However, there were no significant differences between the CKD groups. There were also no group differences in SBP and PP (p ≥ 0.13), although there was a trend for SBP centile (p = 0.08).The DBP, DBP centile and MBP were significantly different between the groups . However, there were no significant differences in SVR between the CKD groups. Importantly, there were no group differences in TAC, local measures of ascending aorta stiffness (AoS and AoC) or cardiac output .There was a significant difference in MVR (a marker of LV remodeling) between the groups .The MVR correlated with all measures of BP , and remained an independent predictor of MVR (p < 0.001) in a model including CKD group (p = 0.01). There was no correlation between MVR and TAC (p = 0.15). Although LVMht2.7 did appear higher in CKD, this did not reach statistical significance . In addition, IRT was higher in severe CKD than in mild CKD patients (p = 0.023).The IRT  was difp = 0.008) as seen in Fig. p = 0.01 and 0.007 respectively).There was a significant association between IRT and MVR . There was no significant difference in longitudinal S′ between groups.Radial S′ velocity, a marker of systolic function, was significantly different between groups (p = 0.016), DBP , but not SBP (p = 0.52). Longitudinal S′ did not significantly correlate with any blood pressures. A model created to study the effects of CKD and DBP (BP with highest univariate correlation) on radial systolic velocity demonstrated that DBP was an independent predictor of radial S′ (p = 0.001) but CKD group was not significant (p = 0.16). Radial S′ also significantly correlated with LVEF .Radial S′ negatively correlated with MBP  on pairwise comparison. However, there were no significant differences between the CKD groups. There were no significant group differences in longitudinal E’ velocity in CKD (Table p = 0.021) and SVR . Two separate models were created to separately study the effects of CKD and DBP or SVR on radial E’. Although CKD group and SVR were independent determinants of Radial E’ , DBP was not a significant predictor (p = 0.19).Radial E’ velocity, a marker of LV relaxation and stiffness, was significantly lower in all CKD groups compared to controls . Unlike IRT, neither was associated with MVR or LVMht2.7 (p > 0.25).In addition, radial and longitudinal E’ correlated negatively with IRT  on pairwise comparison. There were no group differences in radial and longitudinal A’ velocities or E/E’.The E’/A’ was different between groups (p = 0.04), MVR  and longer IRT . On multi-variable regression, eGFR remained a significant determinant of MVR  and IRT  after adjustment for MBP (p ≥ 0.06). In a model with IRT as dependant variable, eGFR trended towards significant  and MVR was significant .Worsening eGFR was associated with higher MBP . These relationships remained significant after adjusting for the effect of afterload (MBP or SVR) in a multi-variable regression model . There were no other significant relationships between eGFR, PTH and Hb with other cardiovascular parameters.Reduced Hb was also associated with a reduced radial function  elevated BP (both MBP and DBP), ii) increased SVR, but no evidence of increased vascular stiffness, iii) higher LV MVR independent of BP, iv) abnormalities of diastolic function suggestive of reduced active relaxation and increased chamber stiffness and v) Reduced systolic velocities with preserved global systolic function. These changes appeared most marked in children with moderate and severe CKD stages.It is well recognized that hypertension is common in pediatric CKD . HoweverOther possible causes of hypertension in CKD are fluid overload or high CO. Although fluid overload is difficult to assess, we did show that RAA (a marker of fluid overload) was normal in our cohort. Furthermore, we also demonstrated that CO was not increased in CKD. Therefore, it is unlikely that these factors are important in the pathogenesis of hypertension in early CKD.In our study, we demonstrated that children in the severest CKD group had increased LV MVR compared to controls and, as eGFR fell, MVR increased. These results suggest that worsening CKD is associated with increased concentric remodelling in children. Interestingly, height indexed LV mass was not statistically different in our population, unlike previous TTE studies. This may be due to the well-recognized overestimation of LV mass using TTE, particularly in patients with CKD .Ventricular remodelling in these children is partly explained by their hypertensive phenotype. However, both CKD group and eGFR remained significant predictors of MVR after controlling for BP. This implies that other ‘uremic’ processes are involved in CKD associated remodelling. Possible ‘uremic’ causes of hypertrophy include: anemia, hyperparathyroidism and sympathetic overactivity , 27, 28.We found conventional transmitral inflow peak E/A to be normal in children with CKD. However, both IRT and radial E’ were abnormal, pointing towards subtle diastolic dysfunction in moderate to severe CKD. In addition, longer IRT was associated with lower eGFR. IRT is a marker of active myocardial relaxation and correlates with invasively measured isovolumic relaxation constant . Previou2.7. Thus, reduced early filling cannot simply be explained by LV hypertrophy. One explanation for reduced ventricular compliance is myocardial fibrosis, which has been demonstrated in several animal models [Early diastolic peak velocity is a marker of both active relaxation and ventricular compliance . Our deml models . Unfortul models . Neverthl models  and thesGlobal systolic function was preserved in CKD patients with normal LVEF. However, radial S′ was reduced in moderate and severe CKD, implying some element of systolic dysfunction in the latter stages of renal disease. These findings are in keeping with previous tissue Doppler imaging and echocardiographic strain studies and illustrate the importance of assessing systolic function in a more sophisticated manner , 35. TheWe have demonstrated that children with CKD exhibit a specific, but subtle cardiovascular phenotype. This phenotype is characterized by: i) increased MVR, ii) increased IRT, iv) reduced radial S′ and E’ and iv) increased SVR. All of these metrics can be evaluated with TTE. In fact, due to its high temporal resolution, it is probably the most accurate method of assessing timing parameters (i.e. IRT) and tissue velocity. However, there are some limitations to TTE. In particular, TTE overestimates LVM  and cannAn important limitation is the relatively older age of the study cohort. Although the entire cohort of CKD patients did include patients from 7 to 18 years of age, the majority of children were between the ages of 9 to 16 years. Thus, the study findings may not be as applicable to younger children. In order to ensure that the study findings can be extrapolated to all age groups, future studies should consider recruiting younger patients.The absence of recent TTE data in the subjects is also a potential limitation in this study. Performing an TTE in tandem may have been informative for the comparison of CMR findings with an established standard clinical investigation. This would have enabled us to confirm our CMR findings of subtle systolic and diastolic impairment with TTE results. Unfortunately, this was not performed as part of the study protocol in order to minimise inconvenience to the study subjects. No recent clinical TTE data were available for comparison in this cohort either. However, despite that, our findings are in agreement with the majority of previous studies in pediatric CKD using TTE as referenced in the paper.Another limitation is our use of mild, moderate and severe CKD grouping instead of the conventional categorization of CKD stages 1–5. This was done to ensure adequate powering for group wise differences. However, the use of conventional CKD groups would be desirable in future larger, multicenter studies.Finally, BP measurements were carried out using an oscillometric sphygmomanometer, which may be less accurate than using manual sphygmomanometer . This waIt is possible to use CMR to comprehensively evaluate cardiac and vascular phenotype in children with CKD. In the future, these novel CMR indices may even be useful for identifying high-risk pediatric CKD patients. More work is needed to determine normative pediatric values. Future prospective studies will also be required to correlate these markers with prognosis in order to predict cardiovascular risk.Additional file 1:This table outlines the clinically relevant blood and urine tests in the mild, moderate and severe CKD groups. (DOCX 17 kb)


Phase analysis of gated myocardial perfusion single-photon emission computed tomography (SPECT) for assessment of left ventricular (LV) dyssynchrony was investigated using the following dedicated software packages: Corridor4DM (4DM), cardioREPO (cREPO), Emory Cardiac Toolbox (ECTb), and quantitative gated SPECT (QGS). The purpose of this study was to evaluate the normal values of 95% histogram bandwidth, phase standard deviation (SD), and entropy and to compare the diagnostic performance of the four software packages. A total of 122 patients with normal myocardial perfusion and cardiac function  74.3 ± 5.7%, and end-diastolic volume (EDV) 83.5 ± 3.6 mL) and 34 patients with suspected LV dyssynchrony  who underwent Tc-99m methoxy-isobutyl-isonitrile/tetrofosmin gated SPECT were retrospectively evaluated. Dyssynchrony indices of the 95% histogram bandwidth, phase SD, and entropy were computed with the four software programs. Diagnostic performance of LV phase dyssynchrony assessments was determined by receiver operator characteristic (ROC) analysis. The area under the ROC curve (AUC) was used to compare the software programs. The optimal cutoff point was determined by ROC curve based on the Youden index.r ≥ 0.73, p < 0.001). ROC AUCs of bandwidth, phase SD, and entropy were ≥0.850, ≥0.858, and ≥0.900, respectively. Moreover, the ROC AUCs of bandwidth, phase SD, and entropy did not significantly differ among the four software programs. Optimal cutoff points for phase parameters were 24°–42° for bandwidth, 8.6°–15.3° for phase SD, and 31–48% for entropy.The average of normal bandwidth significantly differed among the four software programs except in the comparison of 4DM and ECTb. Moreover, the normal phase SD significantly differed among the four software programs except in the comparison of cREPO and ECTb. The software programs showed high correlation levels for bandwidth, phase SD, and entropy (Although the optimal cutoff value for determining LV phase dyssynchrony by ROC analysis varied depending on the use of the different software programs, all software programs can be used reliably for phase dyssynchrony analysis. Cardiac resynchronization therapy (CRT) has been shown to be beneficial for patients with severe heart failure (HF) who do not respond to treatment with medications. The three eligibility criteria for CRT are a New York Heart Association (NYHA) functional class III or IV, left ventricular ejection fraction (LVEF) ≤35%, and QRS duration >120 ms in cardiac echocardiography .In order to improve the selection criteria for patients with HF to predict sufficient response to CRT, assessment of left ventricular (LV) mechanical dyssynchrony has been proposed. The LV mechanical dyssynchrony of patients with HF can be assessed using noninvasive imaging modalities such as an echocardiography with tissue Doppler imaging , 4 and aThe purpose of this study was to clarify the normal values of 95% histogram bandwidth, phase standard deviation (SD), and entropy and to compare the diagnostic performance of the following software programs in phase analysis for identifying LV phase dyssynchrony: 4DM, cREPO, ECTb, and QGS.99mTc-sestamibi (MIBI) or 99mTc-tetrofosmin GMPS were retrospectively enrolled. Of these 156 patients, 122 were diagnosed as having normal perfusion (summed stress score ≤3) and cardiac function (EF ≥ 50%). The data for these patients were included in a Japanese normal database generated by the Japanese Society of Nuclear Medicine working group (JSNM-WG). The patient selection criteria for generating the normal database have been summarized elsewhere [n = 15), screening for the left bundle branch block (BBB) (n = 15), right BBB (n = 3), and pulseless ventricular tachycardia (n = 1). Of 34 patients, 15 patients were diagnosed as having heart failure with NYHA class III or IV symptoms. These clinical diagnoses were made separately in the Department of Cardiology. Consequently, we used these clinical diagnoses for discrimination between normal and abnormal phase distributions in GMPS data. The patient characteristics are shown in Table A total of 156 patients, who underwent lsewhere –22. The 99mTc was set as a 15% energy window centered at 140 keV. The acquisition pixel size was 6.6 mm in a 64 × 64 matrix. Sixteen frames per cardiac cycle were used during data acquisition in GMPS. A circular orbit of the gamma cameras was adopted for 360° SPECT image acquisition with 60 projections. 99mTc-MIBI or 99mTc-tetrofosmin of 300–370 MBq was injected intravenously. The time per view of the SPECT acquisitions were 35 s (360° acquisition with 60 views), 50 s (180° acquisition with 32 views), and 60 s (180° acquisition with 30 views). The detailed acquisition conditions for the JSNM-WG normal database have been summarized elsewhere [With regard to the image acquisition condition for patients with suspected LV dyssynchrony, GMPS was performed with a dual-head gamma camera  equipped with a low-energy high-resolution (LEHR) collimator. A photopeak window of lsewhere –22.The LVEF, end-diastolic volume (LVEDV), and end-systolic volume (LVESV) were automatically calculated with a cREPO software program. A histogram of phase distribution in the whole LV was computed from rest GMPS data. The phase SD and bandwidth were calculated with 4DM, cREPO, ECTb, and QGS programs. The bandwidth was expressed as 95% width of the phase histogram . Entropyt test was used to analyze the differences among continuous variables. For the paired continuous variables, a paired t test was used to analyze the differences. Linear regression analysis was used to explain the relationship between two continuous variables. The Tukey-Kramer method was used for multiple comparisons of the bandwidth and phase SD among software programs. The Bland-Altman analysis was used for the assessment of the agreement. The receiver operating characteristic (ROC) area under the curve (AUC) values were expressed as mean ± standard error of the mean. Subsequently, the optimal cutoff points were determined by ROC curve based on the Youden index [p values ≤0.05 were considered significant. These analyses were performed using MedCalc version 14.12.0  and JMP version 11.2.1 .All continuous values are expressed as a mean ± standard deviation. Student en index . All stap = 0.029). With regard to LV function and phase distribution, the LVEF significantly decreased, and LVEDV, LVESV, bandwidth, phase SD, and entropy significantly increased in patients with suspected LV dyssynchrony in comparison with normal patients (p < 0.0001). The patients with suspected LV phase dyssynchrony had moderate myocardial perfusion abnormalities . When we calculated LVEF values in 15 patients with HF and 19 patients with echocardiographic abnormality, mean EF values were 38 ± 14% for those with HF and 64 ± 11% for those with electrocardiographic abnormality (p < 0.0001). Thus, this result showed that the patients with suspected LV dyssynchrony had slight to severe cardiac function abnormalities.The mean age of patients with suspected LV dyssynchrony was slightly higher than that of those with normal perfusion ). The mean phase SD also significantly differed among the four software programs , and ECTb and cREPO (p = n. s.)). A significant difference was observed between the mean entropies calculated by QGS and cREPO .The phase distribution of patients with normal perfusion is shown in Fig. p < 0.0001).The phase distribution of patients with suspected LV dyssynchrony is shown in Fig. r = 0.87), cREPO (r = 0.93), and QGS (r = 0.83). The Bland-Altman analysis revealed that the mean differences were 4.7°, 13.1°, and −9.2° for 4DM vs. ECTb, cREPO vs. ECTb, and QGS vs. ECTb, respectively. The 95% limits of agreement (LoA) between cREPO and ECTb was narrower than those between 4DM and ECTb, and between QGS and ECTb.The relationship and agreement among bandwidths obtained from the four software programs are shown in Fig. r = 0.83), cREPO (r = 0.79), and QGS (r = 0.73). The Bland-Altman plots of the three software programs based on ECTb showed negative mean differences of −2.9°, −1.0°, and −5.3° for 4DM, cREPO, and QGS, respectively. The 95% LoA of QGS exhibited slightly wide variation in comparison with 4DM and cREPO.The relationship and agreement among phase SDs obtained from the four software programs are shown in Fig. r = 0.82), the linear regression line was shifted to the right by 16.6%. The Bland-Altman analysis revealed that the mean of the difference was −17.7% and the 95% LoA ranged from −34.7 to −0.6%.The relationship and agreement between entropies obtained from QGS and cREPO are shown in Fig. The ROC curve and its AUC are shown in Fig. There were also no significant differences in AUC analysis in terms of the phase SD derived from the four software programs . The sensitivity, specificity, and accuracy of the phase SD ranged from 76 to 79%, 83 to 89%, and 80 to 84%, respectively. The lowest and highest cutoff points of phase SD were 8.6° for QGS and 15.3° for ECTb, respectively. The percentages of patients who were classified differently using cutoff points for phase SD were 18% for 4DM, 18% for cREPO, 21% for ECTb, and 14% for QGS.No significant difference in AUC of entropy was observed between QGS (0.915 ± 0.034) and cREPO (0.900 ± 0.034). The sensitivity, specificity, and accuracy of an entropy were 82, 87, and 85% for QGS, and 79, 87, and 83% for cREPO, respectively. The cutoff point of entropy obtained by cREPO was higher than that obtained by QGS. The percentages of patients who were classified differently using cutoff points for entropy were 15% for cREPO and 14% for QGS.p = 0.0047). Regarding the phase entropies obtained by QGS and cREPO, the ROC AUC of entropy showed significantly higher values than that of bandwidth in cREPO (p = 0.008) and that of phase SD in QGS (p = 0.016).The diagnostic performance of the bandwidth assessment was equivalent to that of the phase SD in 4DM, cREPO, and ECTb except for QGS  and phase SD . Furthermore, when we additionally computed bandwidth and phase SD using the ECTb software program in each hospital, there were no significant differences among the four hospitals in bandwidths ) and phase . Although there were no significant differences among four hospitals in normal bandwidth and phase SD, further clinical validation might be required to determine whether to harmonize the acquisition methodologies and gamma cameras in multicenter study or not.The Japanese normal database consists of 122 normal patients enrolled from four hospitals. Various gamma cameras with LEHR and Vertex general-purpose (VXGP) collimators manufactured by ADAC, Elscint, Toshiba, and SIEMENS were used in the four hospitals. The acquisition conditions of myocardial perfusion SPECT were essentially the same in the four hospitals. All gated SPECT acquisitions were performed using 64 × 64 matrix with 16 frames per RR interval. However, 180 or 360° circular rotation of gamma cameras with step and shoot mode was used. When we calculated the normal bandwidth and phase SD using the ECTb software program derived from 180 or 360° SPECT acquisition in the four hospitals, there were no significant differences in bandwidth (30.0° ± 8.5° vs. 27.2° ± 9.3°; We only performed phase analysis of rest GMPS in this study. Since myocardial perfusion count statistics vary under stress and rest conditions, ROC AUCs and cutoff values will be different under stress conditions. Furthermore, sex differences in bandwidth, phase SD, and entropy have been reported , 30, 31.The mean bandwidth, phase SD, and entropy significantly differed in 4DM, cREPO, ECTb, and QGS software programs in patients with normal perfusion and cardiac function. The LV dyssynchrony parameters of bandwidth, phase SD, and entropy obtained by 4DM, cREPO, and QGS were highly correlated with those by ECTb. Although the optimal cutoff values of bandwidth, phase SD, and entropy were variable depending on the software programs, the diagnostic performance by ROC analysis was equivalent. All four software programs can be used reliably for phase analysis in GMPS.


Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal α–1,4-glucosidase leading to accumulation of glycogen in target tissues with progressive organ failure. While the early infantile-onset form is characterized by early severe hypertrophic cardiomyopathy with cardiac and respiratory failure, clinically relevant cardiomyopathy seems to be uncommon in patients with late-onset Pompe disease, and the prevalence and nature of myocardial abnormalities are still to be clarified.Seventeen patients with genetically proven late-onset Pompe disease  and 18 age- and gender-matched healthy controls  underwent comprehensive cardiovascular magnetic resonance (CMR) including conventional and advanced techniques: cine and feature tracking-based strain imaging for depiction of (even subtle) systolic LV dysfunction as well as late gadolinium enhancement (LGE) and myocardial extracellular volume fraction (ECV) quantification for focal and diffuse fibrosis detection.All patients had normal left ventricular (LV) and right ventricular (RV) volumes and normal LV and RV ejection fraction. In comparison to healthy controls, neither conventional cine nor advanced feature-tracking based-strain imaging could depict any  myocardial systolic dysfunction. Three (18%) of the patients had non-ischemic LGE in the basal inferolateral wall and 21% demonstrated elevated global ECV values suggestive of interstitial myocardial fibrosis. Non-specific abnormalities such as left atrial (LA) dilatation were present in two patients, while LV hypertrophy was seen only in one. Two of the three LGE-positive patients were also hypertensive and demonstrated high global ECV values (>30%) in addition to dilated LA. After a median follow-up of 25 (11–29) months, only one cardiovascular event occurred: one of the LGE-positive patients with a high cardiovascular risk profile suffered an acute coronary syndrome.In contrast to the early infantile-onset form of Pompe disease, mild and rather non-specific cardiac abnormalities can be detected by CMR only in a small proportion of patients with late-onset Pompe disease. The observed structural abnormalities seem to result from an interplay between the storage disease and other comorbidities and they did not affect short-term to mid-term prognosis in adult Pompe patients. Glycogen storage disease type II or Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme α–1,4-glucosidase (GAA) leading to accumulation of glycogen resulting in lysosomal dysfunction, autophagy, and progressive tissue damage . SeveritCardiovascular magnetic resonance (CMR) is a highly sensitive tool for detection of functional and structural myocardial abnormalities in both ischemic and non-ischemic cardiomyopathies . In addiThe aim of the present study was to look for even subclinical myocardial involvement by means of comprehensive CMR, including conventional and advanced techniques, in a population of patients with LOPD and no previous history of cardiac disease.GAA gene. All patients underwent detailed cardiac and neurologic evaluation including comprehensive CMR studies. In patients receiving home ventilatory support due to severe respiratory muscle weakness, CMR was performed using non-invasive ventilation (NIV) during the procedure. Exclusion criteria were inability to lie flat and perform the required breathholds as well as contraindications to CMR or to gadolinium contrast administration. Additionally, 18 age- and gender-matched healthy subjects  were included and represented the control group. All patients were periodically followed up in three months intervals. Any cardiovascular event, including heart failure, acute coronary syndromes, detection of arrhythmia, any cardiac hospitalization and cardiac death, was documented.Seventeen patients with known LOPD  were prospectively enrolled between July 2013 and March 2016. Diagnosis was genetically confirmed in all patients by detection of two pathogenic mutations of the ECG-gated CMR studies were performed on 1.5 T scanners  using commercially available cardiac software, electrocardiographic triggering, and cardiac-dedicated surface coils. Cine-imaging was performed using a steady-state-free-precession (SSFP) sequence in three long-axis slices  and a stack of short-axis slices completely covering the LV. LGE imaging was performed using a T1-weighted inversion recovery gradient-echo sequence 10–15 min after intravenous contrast administration (0.10 mmol/kg Magnevist®) in the same imaging planes as the cine-images. For ECV imaging, T1 measurements were made using a Modified Look-Locker inversion recovery (MOLLI) sequence before and 15–20 min after intravenous contrast (following LGE-imaging) as described elsewhere .2 in men and ≥ 27 cm2 in women defined as LA dilatation [CMR analysis was performed off-line by two experienced readers. Ventricular volumes, ejection fraction and LV mass were derived by contouring endo- and epicardial borders on the short-axis cine images and indexed to body surface area. The papillary muscles were included in the LV cavity. LV hypertrophy was considered present whenever maximal end-diastolic wall thickness was ≥ 13 mm in men and ≥ 12 mm in women. The ratio of LV mass to end-diastolic volume was used as an index of concentric hypertrophy [latation . LGE prelatation .http://rsbweb.nih.gov/ij/) software as previously described [For myocardial ECV calculation, motion corrected pre- and post-contrast T1 pixel maps, automatically generated by the scanner after each MOLLI acquisition, were used for processing with Image J . Firstly, landmarks for LV base  and apex were defined in all three long-axis slices at end-diastole. Following, endocardial and epicardial borders were manually delineated in the end-diastolic frame in the three long-axis slices and in the short-axis stack, from the most basal slice without trough plane distortion from the LV outflow tract to the most apical one. Both the landmarks and contours were automatically propagated through the cardiac cycle and manually corrected in case of inaccuracies. Global peak systolic longitudinal strain (GLS) was derived from the long-axis cines, while short-axis cines were used to derive global peak circumferential (GCS) and radial strains (GRS) .p-value ≤ 0.05 was considered statistically significant.Continuous variables with normal distribution are expressed as mean and standard deviation (SD). Skewed variables were expressed as median and interquartile range (IQR). Categorical variables are expressed as frequency with percentage. t-Student test was used for comparison of normally distributed characteristics between patients and controls. Levene’s test was used for testing equality of variances. The chi-square test with Yate’s correction was used to compare non-continuous variables expressed as proportions. Statistical analysis was performed using SPSS software for Windows . A n = 11). Six patients with LOPD (35%) had known hypercholesterolemia, significantly more frequent compared to controls. Additionally, three patients (18%) had arterial hypertension, all under pharmacological treatment, and two patients had diabetes in comparison to none of the controls. None of the patients with LOPD had known cardiac disease at study inclusion.General characteristics of patients and healthy controls are shown in Table n = 14). Upright forced vital capacity (FVC) as measured using a handheld electronic spirometer was reduced to 62.0% ± 29.2% from the predicted value. Five patients (29%) showed normal FVC, and eight individuals (47%) already received nighttime NIV prior to enrollment. Twelve patients (71%) had been receiving ERT in a standard dosage  for 72 months on average (29–83 months).As illustrated in Table n = 3) of the patients showed LA dilatation compared to none of the controls (p = NS). Moreover, three patients (18%) with adult onset of disease, had LGE with a non-ischemic pattern, located mid-wall in the basal inferolateral segment . Some minor differences were measured in the Pompe group in comparison to the control group regarding GCS  and GRS . Moreover, within the Pompe group both GCS and GRS were relatively higher in hypertensive compared to normotensive patients . However, all obtained global strain values were within normal range in both groups.Regarding functional  parameters Table , there wn = 14) and controls (n = 16) in whom successful pre- and post-contrast T1-mapping was achieved . The non-significant differences were unchanged when looking at septal and lateral wall (LW) ECV values. Increased global ECV values (>30%) were found in three (21%) of the Pompe patients - but in none of the controls. Among these three, two were also LGE-positive. However, the increase in ECV involved equally the septum and mid-ventricular LV lateral wall, in areas where no LGE could be visually depicted.There was no significant difference in global ECV between Pompe patients . During this follow-up period, one LGE-positive patient with a high cardiovascular risk profile  experienced an acute coronary syndrome with subsequent diagnosis of two-vessel coronary artery disease, 23 months after inclusion to the study. No other cardiovascular events were registered in the above time interval.To the best of our knowledge, this is the first study aiming to detect even subclinical myocardial involvement by means of comprehensive CMR, including conventional and advanced techniques — in a population of adult patients with LOPD and no previous history of cardiac disease. The major findings of this study can be summarized as follows and are in contrast to previous findings in early infantile-onset Pompe disease : (i) neiA study using state-of-the-art CMR of functional and/or structural myocardial abnormalities in LOPD was necessary since previous studies  showed rather heterogeneous and inconsistent results –8. In thIn our present study, non-ischemic LGE was present in a small proportion of patients and its cause is debatable. A similar intramural LGE-pattern in the basal LV inferolateral wall has already been described in patients with impaired cellular energy metabolism due to genetic mitochondrial myopathy and seems to be at least partially related to a regional increase in LV wall stress . HoweverTaken together, in a small proportion of patients with LOPD mild and non-specific cardiac abnormalities can be detected by CMR and they possibly result from an interplay between glycogen storage and concomitant disease. No clear impact of the findings on short-term to mid-term prognosis was found. However, their long-term consequences remain uncertain and yet to be clarified. Nevertheless, even mild cardiac involvement is only rarely observed in patients with LOPD and does not seem to be of any prognostic value. Therefore, comprehensive CMR studies are not routinely required in these patients from a clinical point-of-view. Obviously, there are no sufficient and specific data to suggest any evidence-based recommendations for cardiac monitoring in LOPD patients. Previous reports addressing e.g. metabolic conditions or rare neuromuscular disorders suggested cardiac evaluations comprising ECG and echocardiography at diagnosis and thereafter at least every 5 years in the case of normal findings. Based on the results of this study, we would recommend a baseline cardiac assessment, including clinical history, physical examination, a 12-lead ECG and echocardiography at diagnosis. In case of normal findings, additional CMR is not required and repeated cardiac evaluations can be performed every 4–5 years. However, in case of abnormal cardiac findings using conventional methods, additional CMR may be scheduled in order to better characterize and assess the nature and clinical value of the respective findings since LOPD patients may also suffer from other (ischemic as well as non-ischemic) diseases.Obviously, the sample size was still small in this study. However, Pompe disease is a rare condition and CMR may be challenging and sometimes impossible in patients with advanced respiratory muscle weakness. Taking this into account, the present study group of 17 patients with comprehensive CMR is noteworthy. Our control group consisted of age- and gender-matched healthy controls, while some of the Pompe patients had comorbidities potentially causing structural myocardial alterations. In addition, chronic respiratory muscle weakness itself may have a structural impact on the heart in affected patients. Echocardiography was not systematically performed at the time of CMR, so comprehensive data on diastolic function were not available. However, it is well known that the diagnosis of diastolic dysfunction by echocardiography has limited reliability, particularly in the initial stages of diastolic dysfunction . FinallyIn contrast to the early infantile-onset form of Pompe disease, mild and rather non-specific cardiac abnormalities can be detected by CMR only in a small proportion of patients with late-onset Pompe disease. The observed structural abnormalities seem to result from an interplay between the storage disease and other comorbidities and they did not affect short-term to mid-term prognosis in patients with LOPD.


Diabetic cardiomyopathy (DCM) is a cardiac dysfunction which affects approximately 12% of diabetic patients, leading to overt heart failure and death. However, there is not an efficient and specific methodology for DCM diagnosis, possibly because molecular mechanisms are not fully elucidated, and it remains asymptomatic for many years. Also, DCM frequently coexists with other comorbidities such as hypertension, obesity, dyslipidemia, and vasculopathies. Thus, human DCM is not specifically identified after heart failure is established. In this sense, echocardiography has been traditionally considered the gold standard imaging test to evaluate the presence of cardiac dysfunction, although other techniques may cover earlier DCM detection by quantification of altered myocardial metabolism and strain. In this sense, Phase-Magnetic Resonance Imaging and 2D/3D-Speckle Tracking Echocardiography may potentially diagnose and stratify diabetic patients. Additionally, this information could be completed with a quantification of specific plasma biomarkers related to related to initial stages of the disease. Cardiotrophin-1, activin A, insulin-like growth factor binding protein-7 (IGFBP-7) and Heart fatty-acid binding protein have demonstrated a stable positive correlation with cardiac hypertrophy, contractibility and steatosis responses. Thus, we suggest a combination of minimally-invasive diagnosis tools for human DCM recognition based on imaging techniques and measurements of related plasma biomarkers. Cardiovascular pathologies are the most common cause of mortality in the world, and diabetes mellitus is one of the major risk factor for cardiovascular disease development . By 2025“frequent and noteworthy complication of diabetes mellitus”. Later in 1972, Rubler et al. introduced the entity named DCM, in order to distinguish this condition from other types of cardiomyopathy [The relationship between diabetes and heart disease has been known for many years, but the first description was made by Leyden et al. in 1881 , when hemyopathy . Nowadaymyopathy . This leDCM affects approximately 12% diabetic patients, disturbing almost 22% subjects over 64 years-old, which represent between 36 and 66 millions of diabetic people, respectively . HoweverThere are different structural and functional modifications in the myocardial tissue after diabetes. These events emerge from metabolic alterations induced by hyperglycemia, insulin resistance and hyperlipidemia Fig. . The lacSeveral animal models have somehow mirrored human DCM to further deep into the molecular mechanisms and key mediators . DiabetiDiastolic dysfunction is defined as a defect in ventricular relaxation in that leads to increase pressures and a subsequent impaired filling during diastole. Systolic dysfunction is the inability of the myocardium to eject the adequate blood volume, what it means, heart exhibits a low EF. Diastolic dysfunction is twice more common in diabetic than non-diabetic subjects, and appears earlier . Also, aAn accurate method to diagnose DCM could include endomyocardial biopsy sampling . The morNowadays, this non-invasive approach is the gold standard diagnostic tool to identify structural cardiac disorders. It provides a reliable identification of the structural abnormalities seen in early stages of DCM, such as impaired diastolic filling and left ventricle hypertrophy. It can also be helpful for the assessment of the progression of the disease and evaluation of treatments . EchocarTwo-dimensional (2D) echocardiography allows to examine cardiac structures and their movement. Furthermore, Döppler technology, that is based on the shift in frequency of ultrasound signals reflected from moving objects, is useful to study blood flow . In addiSince tissue has a greater reflectivity and slower motion that blood flow, TDI applies filters that exclude high velocities and low-intensity reflectors  to quantify velocities through myocardial tissue. Thus, TDI allows measurements of motion during cardiac cycle,analogous to the conventional Döppler . In thisThis procedure is based in the increased reflectivity of intravenous contrast agents (microbubbles) due to the differential reflection of the contained gas compared with surrounding blood and tissue.Thus, ventricular opacification enhances endocardial borders by delineating anatomy, leading to higher accuracy of ventricular size and, more importantly, ventricular motion . The addThis modality of Echo is focused on the acoustic properties of the heart, which are modified when fibrosis is present. A decrease in cyclic variation index allows to diagnose early fibrosis, and also, hypertrophy. Although there are no data in experimental DCM, Pérez et al.  characteCurrent generation 3D-Echo allows for collection of a full pyramidal data set in real time (opposite to the triangular data set of the 2D technique). 3D-Echo provides several advantages over conventional ultrasound methodology since it can evaluate ventricles with abnormal shapes or mobility. It also overcomes disadvantages of 2D-Echo by reducing calculation errors and interferences, and increasing the visualization . 3D-Echo2+ transients delay [STE is a relatively new technique to achieve myocardial mechanical deformation (strain and strain rate). STE overcomes major drawbacks of conventional techniques  such as inter/intra-observer variability, angle dependence or noise interference . It usests delay . In T1DMts delay . Recentlts delay . HoweverCardiac MRI can be also useful for DCM diagnosis. In contrast to echocardiography, MRI operates with greater spatial and temporal resolution to evaluate chamber size, left ventricular EF and myocardial mass distribution. MRI provides extra information about myocardial fibrosis and subclinical ischemia, as premature parameters of cardiac dysfunction. There are two main pulse-sequence MRI defined by the relaxation properties of the different tissues, known as T1 and T2 weighted, that allow the characterization of the tissues. In T1-weighted imaging, tissue regions with high fat content or fibrosis appear bright, whereas in T2-weighted imaging those areas with an increase in the water content look bright. Thus, MRI attains also higher characterization of regional and local systolic contractility , throughGradient-Echo-MRI creates a cine display about different moments of the cardiac cycle by combining radiofrequency pulses with electrocardiogram . Thus, MPhase contrast imaging is an MRI technique that can be used to visualise moving fluid and quantify the velocity in a certain area . Mitral valve inflow velocities, early deceleration time, and pulmonary vein flow velocities are diastolic parameters that can be measured by phase-contrast MRI. Phase-contrast-MRI can obtain images under any circumstance without influence of breathing and minimal variability . The dirThis technology uses radiofrequency pulses of the myocardium to determine cardiac deformation along cardiac cycles through strain rates and torsion recoveries . Tagged-However, MRI may not be available to all patients, and has some limitations. It may underestimate diastolic dysfunction, cannot be compatible with some pacemakers or implantable desfibrilators, and may produce claustrophobia in some patiens. Also, in animals, MRI requires anesthesia, which could interfere with cardiac performance .MsCT uses volumetric methods to obtain ventricular function parameters. End-systolic and -diastolic volume are calculated pixel-by-pixel in different cardiac rotations arranged and reconstructed by an automated software. Small segments of data are collected along several cardiac cycles to generate a final image of computed tomography . High teThese techniques focus on cardiac autonomic dysfunction, as a common finding in early stages of diabetes, as occurs during impaired glucose tolerance, where heart rate and myocardial blood flow may be disturbed.G-SPECT provides simultaneous assessment of cardiac perfusion and left ventricular function by using labeled myocardial perfusion agents, providing real information about ventricular function in 3D, wall thickening, motion, and diastolic parameters . G-SPECT18Fluoro-desoxyglucose as a tracer, revealed a decrease of myocardial glucose utilization and increased fatty acids oxidation, in association with impaired myocardial function [18Fluoro-desoxyglucose itself may constitute a drawback for diabetic patients with impairment in glucose uptake.Similarly, PET scan has been proposed to diagnose DCM, in special, for those subjects with obesity or advanced left ventricular dysfunction and coronary artery disease, who cannot be analysed by G-SPECT . Asymptofunction . In T2DMfunction . HoweverSeveral efforts have been made to improve DCM detection by non-invasive quantification of biomarkers in body fluids such as urine, saliva, semen or tears, but all of them were not conclusive . HoweverNon-physiological cardiac hypertrophy is adaptive and compensatory in DCM. This cellular growth presents as increased myocardial cell surface area, protein synthesis and reactivation of foetal genes . However, in the long term, hypertrophy leads loss of function and death of cardiomyocytes, favoring HF. Thus, a premature detection of pro-hypertrophic factors could be helpful to diagnose early DCM Fig. . In thisIn T1DM patients, high circulating NT-proBNP levels identify left ventricular systolic dysfunction in 96% cases , whereasThus, new prospective pro-hypertrophic biomarkers are needed for DCM detection. In this regard, cardiotrophin-1 (CT-1), a member of the gp130 cytokine family, is mainly released from cardiomyocytes after oxidative and mechanical stress or RAA system stimulation  Troponins have been related with myocardial contractility in different cardiomyopathies. This multiprotein complex is constituted by Troponin I (TnI), C (TnC) and T (TnT) in all striated muscles. Troponin controls calcium mediated interaction between actin and myosin Fig. . In partThus, new prospective biomarkers related with the contractile function of the cardiomyocyte are needed for DCM detection. For this purpose, EAT can release autocrine and paracrine molecules Fig. . InteresFat accumulation in the myocardium may be a protective response to provide a store of fuel for subsequent oxidation and to prevent exposure to toxic lipid metabolites such as ceramides. However, in DCM, a chronic imbalance of lipid storage versus lipid oxidation may lead to mechanical dysfunction . QuantifHfabp is a cardiac cytosolic protein that acts transporting fatty acids to the mitochondria, for degradation and ATP consecution Fig. . After lCardiac transforming growth factor beta (TGFβ) has been associated with the fibrotic degree in DCM . TGFβ acIn addition, cardiac fibroblasts could play a critical role in maintaining normal cardiac function, as well as in cardiac remodeling during pathological conditions such as DCM. Fibroblasts undergo phenotypic transition to myofibroblastic cells for ECM protein expression . In thisA more forthcoming biomarker may be linked to the fibrotic, insulin-resistance and hypertrophic components of DCM Fig. . InsulinIdeally, the presence of DCM should be investigated in both T1DM and T2DM patients when still asymptomatic. Thus, alterations in cardiac metabolism and myocardial strain in the myocardium, could be identified as early events in DCM. For this purpose, Phase-MRI could quantify metabolic disruptions, in spite of potential claustrophobia or incompatibility with pacemakers in some patients, and 2D/3D-STE may detect longitudinal and circumferential myocardial strains. In addition, imaging approaches may be complemented with a minimally-invasive quantification of specific plasma biomarkers. Previous reports showed that a quantification of NT-proBNP combined with 2D-Echo-Döppler imaging was more reliable to diagnose DCM in T2DM patients than any of them alone . FurtherMoreover, early diagnosis of DCM could allow not only a reliable assessment of this pathology, but also, the use of preventive strategies to slow or avoid overt heart failure. For example, a DPP-4 inhibitor triggered beneficial effects on fatty acid uptake and oxidation, and prevention of diastolic dysfunction of T1DM rats . In this


The aim of this study was to assess the changes in cardiac and hepatic iron overload and in morpho-functional cardiac parameters by Magnetic Resonance Imaging (MRI) in transfusion-dependent thalassemia patients who got pregnant and interrupted their chelation treatment.Among the 956 women with hemoglobinopathies in reproductive age enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) project, we selected 17 women with thalassemia  who had a pregnancy with successful delivery and who performed a MRI scan before and after the pregnancy.Myocardial and liver iron overload were measured by T2* multiecho technique. Atrial dimensions and biventricular function were quantified by cine imagesThe pre-pregnancy MRI was performed 15.02 ± 5.31 months before the delivery while the post-partum MRI was performed 5.73 ± 4.45 months later.For 16 new-mothers the post-partum MRI was performed after the restart of the chelation therapy, specifically 3.95 ± 4.10 months later. One new-mother performed the post-partum MRI about 3 months before restarting the chelation therapy.The table shows the MRI parameters at the two MRIs.The pre-pregnancy and the post-partum global heart T2* values and number of pathological segments were comparable. Two patients with a normal global heart T2* value (>20 ms) before pregnancy showed a pathological post-partum value.After pregnancy there was a significant increase of MRI liver iron concentration (LIC) values. At the pre-partum MRI six (35.3%) patients had a MRI LIC < 3 mg/g/dw while at the post-partum MRI all patients had a pathological MRI LIC.Among the biventricular volumetric and functional parameters, there was a significant increase of right ventricular (RV) end-systolic volume index and a significant reduction of RV ejection fraction.In some transfusion-dependent patients, cessation of chelation therapy allows rapid iron overload. Pregnant women with thalassemia should be monitored carefully for iron loading and cardiac status before they embark upon a pregnancy and afterwards and consideration should be given to offering desferrioxamine chelation therapy immediately after delivery. In women showing severe iron overload before pregnancy desferrioxamine should be started after the middle of the second trimester. The negative impact on the RV parameters could reflect the effect of the high cardiac output state independent of the physiological changes during pregnancy.