Patients with end stage renal disease (ESRD) suffer high mortality from arrhythmias linked to fibrosis, but are contraindicated to late gadolinium enhancement magnetic resonance imaging (MRI). We present a quantitative method for gadolinium-free cardiac fibrosis imaging using magnetization transfer (MT) weighted MRI, and probe correlations with widely used surrogate markers including cardiac structure and contractile function in patients with ESRD. In a sub-group of patients who returned for follow-up imaging after one year, we examine the correlation between changes in fibrosis and ventricular structure/function. Quantification of changes in MT revealed significantly greater fibrotic burden in patients with ESRD compared to a healthy age matched control cohort. Ventricular mechanics, including circumferential strain and diastolic strain rate were unchanged in patients with ESRD. No correlation was observed between fibrotic burden and concomitant measures of either circumferential or longitudinal strains or strain rates. However, among patients who returned for follow up examination a strong correlation existed between initial fibrotic burden and subsequent loss of contractile function. Gadolinium-free myocardial fibrosis imaging in patients with ESRD revealed a complex and longitudinal, not contemporary, association between fibrosis and ventricular contractile function. Increasing evidence suggests a link between left ventricular (LV) hypertrophy3 and/or fibrosis6 to fatal arrhythmias and heightened mortality rates in patients with ESRD. While cardiac magnetic resonance imaging (CMR) with gadolinium contrast agents is the clinical standard for fibrosis imaging9, gadolinium agents are contraindicated in patients with ESRD10. In place of direct measurement of tissue fibrosis, measurements of both ventricular structure (LV hypertrophy) and mechanical function including reduced global longitudinal strain (GLS) and diastolic strain rate are used in patients with ESRD11. Consequently, investigations into molecular mechanisms of cardiac fibrosis, the role of fibrosis in promoting adverse outcomes, and potential longitudinal treatments in ESRD all rely on either repeated invasive biopsies or surrogate measures of fibrosis.Sudden cardiac death and fatal arrhythmias are leading causes of mortality for patients on routine hemodialysis for end stage renal disease (ESRD)12. In patients referred for diagnostic imaging with gadolinium, the normalized signal difference between pairs of differentially MT-weighted bSSFP images (ΔS/So) correlated with the severity of fibrosis when assessed using gadolinium based techniques as a standard12. In the current study we expand this method for whole heart quantitative fibrosis imaging in patients with ESRD without bone mineral density loss over one year. We present a method by which to measure global fibrotic burden based on changes in the distribution of ΔS/So values, termed divergence. We probe correlations between fibrotic burden and ventricular hypertrophy or cardiac mechanics. Finally, in a sub-group of patients who returned for follow-up imaging after 1 year we demonstrate quantitative changes in fibrotic burden and examine correlations with changes in left ventricular structure and function.In a prior cardiac magnetic resonance imaging study we demonstrated a gadolinium-free approach to identify cardiac fibrosis based on changes in magnetization transfer (MT) weighting on cine balanced steady state free precession (bSSFP) images13. Demographics for patients with ESRD (n = 29) and healthy controls (n = 33) are detailed in Table Patients with ESRD were recruited from within an ongoing study at our institutionESRD n = 9 and heao values, particularly in the septum and towards the base of the left ventricle. The color scheme for presentation of ΔS/So maps was previously chosen to emulate late gadolinium enhancement, with healthy myocardium appearing dark and densely fibrotic and edematous myocardium appearing bright white12. The complete data from a representative healthy control is shown in Supplemental Fig. o values were significantly higher in ESRD (145 ± 17%) compared to controls  and divergence values  did not change substantially from baseline measurements. However, significant heterogeneity was observed between individuals. Specifically, four individuals demonstrated moderate increases in ΔS/So across a large spatial area that are consistent with increased diffuse fibrosis  or GLS , mass to volume ratio , global longitudinal strain , circumferential diastolic strain rate , or longitudinal diastolic strain rate . While the correlations between divergence and LVMI , mass to volume ratio , global longitudinal strain , and both circumferential diastolic strain rate  and longitudinal diastolic strain rate  were greater after one year, all failed to reach statistical significance in a small sample size.Although divergence and ventricular structure/mechanics were not concomitantly correlated, there was a significant correlation between initial divergence values and corresponding changes in both circumferential and longitudinal diastolic strain rates over one year Table . A simil1. Prior studies using excised tissue6 and CMR with gadolinium14 established cardiac fibrosis as a potential substrate of arrhythmia and sudden death in ESRD15. With contraindications to gadolinium in place, ventricular hypertrophy and cardiac mechanics are often used as surrogate imaging markers of cardiac fibrosis, and are also targets for pharmacological reversal in ESRD18. In this study we used an MT-weighted CMR technique to quantify global ventricular extracellular matrix expansion in patients with ESRD. While we found that patients with ESRD with heightened fibrosis often demonstrate ventricular hypertrophy and attenuated longitudinal and diastolic contractile function, such structural and mechanical measurements were often similarly altered in patients without fibrosis. Additionally, while fibrotic burden was not concomitantly correlated with either ventricular hypertrophy or attenuated mechanical function, greater divergence values at initial examination correlated strongly with subsequent reductions in diastolic strain rates over one year. Further, attenuated initial global longitudinal strain correlated strongly with subsequent increases in fibrotic burden over the same period. Importantly, overall changes in longitudinal diastolic strain rates were highly correlated to changes in LVMI and closely mirrored by changes in fibrotic burden. Together, these findings highlight the complex interplay between global structural and functional changes and local changes in myocardial fibrotic burden in the setting of ESRD.Nearly 40% of mortality among patients with ESRD is attributed to arrhythmias and sudden cardiac deathet al.4 used gadolinium contrast agents to identify three prevailing enhancement patterns in patients with ESRD including thin scar from prior myocardial infarction, diffuse enhancement, and focal fibrosis at a right ventricular insertion point. Similarly, Mark et al. observed patterns of thin scar or diffuse enhancement through various regions of the left ventricle in most patients with ESRD5. Our previous validation of MT-weighted CMR revealed a strong correlation between elevated ΔS/So values and late gadolinium enhancement tissue status12, and in this study we observed patterns of elevated ΔS/So similar to the three prevailing patterns described by Schietinger and colleagues  and associated with poorer prognosis17. In agreement with prior studies21, we observed substantial hypertrophy in patients with ESRD, yet only a moderate correlation was observed between simultaneous measurements of LVMI and divergence. Similarly, reduced global longitudinal strain in patients with ESRD has been demonstrated using both CMR22 and echocardiography25. While we also observed reduced mean GLS in patients with ESRD compared to healthy controls, most values remained well within the normal variation of healthy cohorts26. Further, comparing divergence against simultaneous measurements of both GLS and circumferential diastolic strain rate failed to reveal meaningful associations, similar to reports in hypertrophic cardiomyopathy27. While ventricular fibrosis and reduced strain have been correlated in individuals without ESRD30, measurement of contractile function in ESRD is complicated by hemodynamic fluctuations due to timing relative to hemodialysis24. Such fluctuations have been demonstrated to introduce sampling bias to the measurement of contractile function with echocardiography32. Further, reduced contractile function has not consistently correlated with either histological measures of fibrosis in the ESRD population32, or heart failure or mortality in patients with ESRD33. A distinct finding of this study is that the change in fibrotic burden over one year was variable among patients with ESRD but correlated with the degree of attenuation of GLS at the time of initial examination. While this may suggest that reduced contractile function promotes cardiac fibrosis, Hayer and colleagues recently reported that noticeable loss of GLS occurred over one year in 30 early-stage chronic kidney disease patients, despite preserved and normal left ventricular mass and extracellular volume11. Further, we observed that loss of contractile function was highly correlated to increases in ventricular mass. Together, these findings highlight the intrinsic difficulty of using discrete measurements to assess whether and how tissue fibrosis, hypertrophy, and loss of contractile function are synergistic or merely concomitant pathological processes in the setting of ESRD.Increased collagen content in fibrotic myocardium is associated with greater tissue stiffness, cardiomyocyte hypertrophy and reduced LV contractile functiono. Third, age-related extracellular matrix expansion34 may have impacted both groups, unrelated to underlying ESRD status. Further, while reflecting proportions within the ESRD population1, group differences in race may have led to imbalanced risk factors and confounded measures of cardiac function2. An additional major limitation to this study is the small sample of patients who returned for follow up examination after one year. Among those who were eligible for follow up  but did not participate in the second scan, many cited deteriorating overall health as a major barrier to participation. Subsequently, a recruitment bias towards healthier patients may have obscured correlations between fibrosis, structure, and function over time that would have been observed in a larger ESRD cohort. It is entirely possible that with a larger cohort we may have seen a strong trend towards universal fibrotic progression among patients with ESRD, or greater concomitant correlations. Further, we did not have the statistical power within this group to examine whether heterogeneity in progression of fibrosis was caused by differences in underlying demographic factors including hemodialysis vintage, comorbidities, or medical history. A larger sample size may have also revealed stronger correlations between initial strain values and subsequent changes. In addition, we did not have access to patient dialysis records and could neither control for, nor examine the potential impact of changes in fluid maintenance between visits.Several limitations to our study should be noted. First, while MT-weighted imaging of cardiac fibrosis has previously been compared to late gadolinium enhancement, it has not been validated directly against histology in large animals or humans. This should be performed as part of further validation of fibrosis in the setting of kidney disease. Further, this study was performed at 1.5 T where the impact of B1 heterogeneity is modest when compared to 3 T. Extension of this technique to 3 T scanners will likely require alternate MT-weighting methods, or restrictive analysis to the septum. In addition, since the initial goal of our study was to probe for tissue fibrosis in patients with ESRD we used healthy age matched adults as our control population. Second, acquisition of image pairs requires two consecutive breath holds. To mitigate the impact of potential motion, image registration was performed prior to calculation of ΔS/SWe applied MT-weighted CMR and developed quantitative methods for myocardial tissue characterization in patients with ESRD. Comparing divergence with LVMI and global longitudinal strain by CMR confirms that the association between extracellular matrix remodeling, cardiomyocyte hypertrophy, and attenuated contractile function is complex. The ability to non-invasively derive all three measures from CMR can empower the study of heart failure, prognosis, and mortality in the setting of ESRD. Future studies could utilize this combination to examine the acute impacts of dialysis initiation, or to test specific biomarkers of fibrotic progression in the setting of ESRD.2 in healthy controls (n = 3), abnormal electrocardiogram (n = 1), discovery of aging related (n = 1) or congenital abnormalities (n = 1), or hardware failures discovered after imaging (n = 5) were additional grounds for exclusion. The protocol was approved by the University of Kentucky Institutional Review Board. All research was performed in accordance with relevant guidelines and regulations.Patients on routine hemodialysis for ESRD were prospectively referred from the University of Kentucky Healthcare Department of Nephrology if they had no arrhythmia nor CMR incompatible metal or devices (n = 33). Healthy volunteers without cardiovascular disease, hypertension, diabetes, obesity, tobacco use, or CMR incompatibilities were prospectively included if within the age range of our patients (n = 44). Voluntary informed consent was obtained prior to participation. Participants were excluded from data analysis if unable to hold their breath or complete the MRI protocol (n = 1 ESRD each). Body mass index >26 kg/m12. During separate end expiratory breath holds, cine bSSFP image pairs were obtained using excitation flip angles of 5° and 45° in a short axis stack from LV base to apex. Parameters included TE: 1.2 ms, TR: 3.2 ms, bandwidth: 930 Hz, matrix: 256 × 256, in-plane resolution: 1.02 × 1.02 mm, slice thickness: 8 mm, and GRAPPA 2.A 12-lead electrocardiogram was conducted prior to MRI. Imaging occurred on non-dialysis days with a 1.5 T Siemens Aera scanner  using an 18-channel body matrix coil and 12-channel spine coil. MT-weighted CMR was completed as previously described35 . Circumferential and longitudinal strains were assessed via custom feature tracking algorithm35 Fig. . Global o /S5° * 100 (%), where S is signal intensity per voxel. Figures are presented with a 2 × 3 median filter and color schemes that emulate late gadolinium enhancement images as described previously12. The LV myocardium was manually segmented and end diastolic unfiltered ΔS/So maps were used for quantitative analysis. Bullseye plots demonstrate mean ΔS/So per sector . Cine image pairs with excitation flip angles of 45° Fig.  and 5°  were rego Fig.  were gentor Fig. . Mean ΔSo. Mann-Whitney U tests compared group body mass index, LVMI, mass:volume ratio, septal thickness, end systolic volume, ejection fraction, QRS duration, QTc interval, GLS, divergence, and serum biomarkers. Baseline and follow-up results were compared using related-samples Wilcoxon signed rank tests for EDV, ESV, and cardiac output. All other results were compared using analysis of variance (ANOVA) with repeated measures. Change in divergence across scans was compared against measures of structure and function using Pearson correlations. Associations of imaging results with measures of structure, function, and serum biomarkers were measured by Pearson correlations. Data are presented as mean ± standard deviation, median [interquartile range], or count (%) where appropriate. P < 0.05 was considered significant.Statistics were computed using SPSS Statistics . Shapiro-Wilk and Levene’s tests assessed normality and homogeneity of variance. Student’s t-tests compared group means for heart rate, end diastolic volume, circumferential diastolic strain rate, and ΔS/SVoluntary informed consent was obtained prior to participation. The protocol was approved by the University of Kentucky Institutional Review Board.Supplemental Data


Aortoiliac occlusive disease (AIOD) affects the systemic vascular resistance and increases the afterload because the left ventricle (LV) must work harder to eject blood into a smaller vascular bed. This study was to determine whether successful revascularization of AIOD is associated with improvement of left ventricular diastolic dysfunction (LVDD).E/E′ ratio.A total of 37 patients with AIOD  were analyzed. The primary endpoint was defined as the change in the mitral E velocity , A velocity , LAVI , E/A ratio , and E′ velocity . However, successful revascularization significantly reduced the E/E′ ratio . Additionally, a significant increase in the A′ velocity  and a decrease in the LA diameter  were noted.There were no significant changes in the E/E′ ratio.Our results show that a successful revascularization of AIOD was associated with an improved  On the other hand, a recent study highlighted a high prevalence of LVDD in patients with peripheral artery disease (PAD). In particular, aortoiliac occlusive disease (AIOD) may result in the progression of LVDD through LV remodeling secondary to an increased afterload. Considering that systemic vascular resistance (SVR) is often used as a measure of the afterload in a clinical setting, severe AIOD might affect the SVR and subsequently increase the afterload because the LV must work harder to eject the blood into the occluded iliac artery. It remains unknown in the published literature whether successful revascularization of severe AIOD improves LVDD, and if so, whether its effect is attributable to the attenuation of LVDD. The current study investigated the effect of successful revascularization on LVDD in patients with AIOD.Left ventricular diastolic dysfunction (LVDD) is usually the result of impaired LV (left ventricular) relaxation with or without reduced restoring forces and increased LV chamber stiffness, which increases the cardiac filling pressure.22.1The study population was retrospectively recruited from consecutive patients who were admitted at 2 university hospitals (between January 2005 and September 2017) and discharged after successful percutaneous revascularization of severe AIOD. The list of these patients was matched with a list of patients with pre-procedural and post-procedural echocardiograms around the time of the revascularization procedure. Patients were excluded if they had a history of acute myocardial infarction or admission due to heart failure (HF) aggravation before checking the follow-up echocardiogram after the revascularization procedure, evidence of critical limb ischemia (CLI) with poor tibial runoff vessels, significant LV hypertrophy at baseline , significant valve diseases , and atrial arrhythmia including atrial fibrillation.This study was conducted in accordance with the Declaration of Helsinki and was approved by our institutional review board.2.2E/E′ ratio, an index of LVDD. The secondary endpoints included the changes in the pulsed-wave Doppler (PWD)-derived trans-mitral filling indices , Tissue Doppler imaging (TDI) derived indices , left ventricular ejection fraction (LVEF), left atrial volume index (LAVI), and improvement on LVDD.The primary endpoint was defined as the change in the mitral 2.3 The PWD-derived trans-mitral velocities were obtained at the mitral leaflet tips. TDI derived indices were acquired in the apical 4-chamber view with the sample positioned at the septal and lateral mitral annulus for determination of the systolic (S′), early diastolic (E′), and late diastolic (A′) velocities. For all parameters, the average of 3 consecutive heartbeats was recorded, and the velocities were recorded at end-expiration. The E′ velocity was determined at each annular site and averaged. The PWD-derived E velocity /TDI-derived E′ velocity (E/E ratio) was calculated to determine the LV filling pressure. The systolic function was evaluated by LVEF using the modified Simpson rule from the biplane 4-chamber and long-axis views. LVDD refers to a disturbance in ventricular relaxation, distensibility or filling regardless of whether the LVEF is normal or depressed and whether the patient is asymptomatic or symptomatic. According to the recently published guideline, LVDD was considered to be present if more than half of the 4 recommended parameters meet the cutoff values for identifying abnormal function. Briefly, the 4 recommended parameters and their abnormal cutoff values are the annular E′ velocity , average E/E′ ratio >14, maximum LAVI >34 mL/m2, and peak TR velocity >2.8 m/s. Improvement of LVDD was defined as any decrease of the baseline E/E′ ratio or any increase of the baseline E′ velocity after the revascularization procedure.The left atrial (LA) diameter was measured in the parasternal long axis view, and the end-systolic LAVI was measured with the biplane area-length method.Severe AIOD was defined as a total or subtotal occlusion of the aortoiliac segment (TASC-II C or D lesions) with several visceral and parietal collateral channels.Coexistent coronary artery disease (CAD) was defined as the presence of any degree of narrowing in at least 1 major coronary arteries on angiogram or computed tomography in the study population.Successful revascularization was defined as revascularization of the occlusive lesion with <30% residual diameter stenosis and absence of dissection impairing blood flow at the final angiographic control.2.4P-value of <.05 was considered to be statistically significant. The analyses were performed using the SPSS version 13 software .The mean (standard deviation) and percentages are reported for continuous and categorical variables, respectively. Logistic regression analysis was performed to identify possible predictors of improvement of LVDD. A 3We identified 80 patients who underwent an endovascular intervention for AIOD. With careful review of the exclusion criteria, 37 patients  were included in the analysis . However, the change of diastolic blood pressure was not different  , A velocity , DT , and LAVI . The E/A ratio, the most commonly used diastolic function parameter in the clinical setting did not yield a significant change . The E′ velocity showed no significant changes during the study period . However, successful revascularization significantly reduced the E/E′ ratio   and a decrease of the LA diameter  were noted. The highest decrease of the E/E′ ratio was observed in a 67-year-old woman with totally occluded bilateral iliac arteries (from 35.1 at baseline to 15.3 at follow up).Changes in the echocardiographic parameters as a result of successful revascularization are shown in Table When it comes to the grade of LVDD, baseline LVDD was present in all patients, with “Grade II, relaxation abnormality” being the most prevalent  and “Grade III, pseudonormalization” in only 13.5% (n = 5). On follow up echocardiogram, 2 patients 5.4%) had worsening, and 31 patients (83.8%) had no change, and 4 patients (10.8%) had improved baseline LVDD . Logistic regression analysis was performed to identify possible predictors of improvement of LVDD. However, we did not observe any significant parameters related to the improvement of LVDD; thus, multivariate analysis was not done.4E/E′ ratio substantially decreased after successful revascularization in patients with AIOD. Changes in other parameters such as the E velocity, E′ velocity, E/A ratio, LVEF, and LAVI were not significant.In the present study, we showed that the E/A ratio, have been the most widely used to evaluate LVDD in the clinical setting, they however are largely influenced by cardiac preload. In contrast, TDI derived indices are known to be a more sensitive tool than the PWV-derived indices for the detection of afterload-related LVDD. The E/E′ ratio is the most reproducible TDI-derived parameter to estimate the LV filling pressure related to LVDD and is the preferred prognostic parameter in patients with LVDD. Although the change in the E′ velocity was not significant, it certainly was the improvement of the E′ velocity  that contributed to the decreased E/E′ ratio after the successful revascularization procedure because the E velocity did not change at all . Afterload reduction followed by a decrease of the LV filling pressure in conjunction with a successful revascularization procedure seems to be the main facilitating mechanism for our result.Echocardiogram has been used as the most important clinical tool in terms of evaluating LVDD. Even though the PWV-derived indices, in particular the ,12 Overall, LVDD is more frequent in patients with AIOD, and the outcome data for this group are very limited. It is most likely, however, that this combination is associated with increased CV morbidity and mortality. Afterload is defined as the force that opposes shortening of the myocardial fibers. The most common descriptor of afterload in the clinical setting is the SVR. Thus, successful revascularization of AIOD may be an attractive method to improve LVDD by its afterload reducing effect. Given these results, it appears that successful revascularization of AIOD may have a beneficial effect on cardiac diastolic function leading to an improved prognosis independent of the symptomatic claudication relieving effect.AIOD is often associated with overt atherosclerosis involving CAD, which may cause subsequent heart failure. Theoretically, elevated aortic stiffness due to an occlusion of the iliac artery increases the LV afterload, and a high pulse pressure impairs the coronary blood flow resulting in hypertension, LV hypertrophy, LVDD, and ultimately overt HF. The circulation distal to an occluded lesion often undergoes collateralization, which reduces the SVR and thereby maintains a normal resting blood flow despite a reduced perfusion pressure. In particular, intact deep femoral artery (DFA) in patients with FP artery disease usually have good collateralization with the smallest increases in the afterload following FP artery occlusion. Thus, the greatest benefit on LVDD from the revascularization procedure would be anticipated in patients with AIOD rather than patients with FP artery disease.A recent study demonstrated the beneficial effect of revascularization on improving LVDD in patients with femoropopliteal (FP) artery disease. A RAAS inhibitor and diuretic may change the LV end diastolic volume and end systolic volume, resulting in an altered LV relaxation rate. However, these medications in this study had been started the day of the procedure or before, and little changed during the study period.One might wonder if medical therapy affects LVDD and works as a confounding factor, since the pharmacological actions of a RAAS inhibitor, diuretic or beta-blocker may affect LVDD. Decreases in the heart rate with a beta-blocker may affect the LVDD properties by increasing the LV relaxation rate. This finding further underscores the potential important value of successful revascularization of AIOD in terms of blood pressure reduction.In the present study, the effect of revascularization procedure on reducing systolic blood pressure was significant. A large artery occlusion produces a strong reflection site which can develop abnormal or premature wave reflection and increase arterial stiffness. This plays an important role in the genesis of hypertension. A RAAS inhibitor and diuretic may change the LV end diastolic volume and end systolic volume, resulting in an altered LV relaxation rate. Meanwhile, of note is that patients with PAD including AIOD but no clinical evidence of CAD have the same relative risk of death from cardiac causes as those whose main diagnosis is CAD. Current recommendations for the treatment of LVDD primarily include control of underlying comorbidities such as hypertension, ventricular rate in atrial fibrillation, pulmonary congestion, and peripheral edema.,18 Based on the result of this study, we suggest that successful revascularization of severe AIOD might be a possible way to reduce the afterload and to improve LVDD.There are several limitations to the present study. First, the number of study patients might have been small to detect the differences. The sample size may therefore be underpowered and accordingly the clinical implications may be limited. Second, we only obtained baseline and follow-up diastolic parameters and therefore, cannot clarify the variability of the diastolic parameters during the course of the study. There may be concern that the diastolic parameters could become altered according to the time of the echocardiographic assessment, which was not standardized in this study. Third, we did not take the length and diameter of the occluded lesion into consideration leading to a heterogeneous sample. Fourth, the pharmacological actions of a RAAS inhibitor, diuretic or beta-blocker may affect LVDD. Decreases in the heart rate with a beta-blocker may affect the LVDD properties by increasing the LV relaxation rate.5E/E′ ratio, and these changes may represent its effect on the afterload reduction.This study shows that successful revascularization of AIOD was associated with the improvement of the Conceptualization: Wonho Kim, Tae Soo Kang.Data curation: Wonho Kim, Tae Soo Kang.Formal analysis: Wonho Kim, Tae Soo Kang.Funding acquisition: Wonho Kim.Investigation: Wonho Kim, Tae Soo Kang.Methodology: Wonho Kim.Project administration: Wonho Kim.Resources: Wonho Kim, Tae Soo Kang.Supervision: Tae Soo Kang.Writing – original draft: Wonho Kim, Tae Soo Kang.


Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is an autosomal dominant and the third most common inherited muscle disease. Cardiac involvement is currently described in several muscular dystrophies (MD), but there are conflicting reports in FSHD1. Mostly, FSHD1 is recognized as MD with infrequent cardiac involvement, but sudden cardiac deaths are reported in single cases.The aim of this study is to investigate whether subclinical cardiac involvement in FSHD1 patients is detectable in preserved left ventricular systolic function applying cardiovascular magnetic resonance (CMR).n = 52, 48 ± 15 years) and compared them with 29 healthy age-matched controls using a 1.5 T CMR scanner. Myocardial tissue differentiation was performed qualitatively using focal fibrosis imaging (late gadolinium enhancement (LGE)), fat imaging (multi-echo sequence for fat/water-separation) and parametric T2- and T1-mapping for quantifying inflammation and diffuse fibrosis. Extracellular volume fraction was calculated. A 12-lead electrocardiogram and 24-h Holter were performed for the assessment of MD-specific Groh-criteria and arrhythmia.We prospectively included patients with genetically confirmed FSHD1 . This was also evident in regions adjacent to focal fibrosis, indicating diffuse fibrosis. Groh-criteria were positive in 1 patient. In Holter, arrhythmic events were recorded in 10/43 subjects (23%).Focal fibrosis by LGE was present in 13 patients , fat infiltration in 7 patients . T2 values did not differ between FSHD1 and healthy controls. Native T1 mapping revealed significantly higher values in patients (global native myocardial T1 values basal: FSHD1: 1012 ± 26 ms vs. controls: 985 ± 28 ms, Patients with FSHD1 and preserved left ventricular ejection fraction present focal and diffuse myocardial injury. Longitudinal multi-center trials are needed to define the impact of myocardial changes as well as a relation between myocardial injury and arrhythmias on long-term prognosis and therapeutic decision-making.ISRCTN13744381.ISRCTN registry with study ID  Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is an autosomal dominant disorder and the third most common inherited muscle disease with an incidence of 1:8.000–1:20.000 . The molCardiac involvement in patients with other neuromuscular diseases (NMD) is more common. It may occur in up to 90% of patients in the general muscular dystrophy (MD) population, leading to heart failure and sudden cardiac death (SCD) . ArrhythFSHD1 is usually recognized as a NMD with infrequent myocardial involvement, but SCD and progressive heart failure are reported . FurtherThe study was approved by the local ethic committee (EA1/169/15) and all subjects gave written informed consent.We prospectively screened 64 patients with FSHD1 of which 58 patients could be included in the study. CMR could not be completely performed in 6 patients: 3 due to arrhythmia , 1 claustrophobia, 1 obesity, 1 known allergy to contrast media. Finally, 52 patients  were analyzed.The diagnosis of FSHD1 was defined as partial loss of D4Z4 macrosatellite repeats units in the subtelomeric region of chromosome 4. While patients with FSHD1 present 1–10 repeats, there are 11–110 repeats in the general population [Patients underwent a cardiological work-up including physical examination and echocardiography to confirm a preserved LVEF. A LVEF lower than 55% was defined as an exclusion criterion .A detailed patient medical history was recorded. Laboratory hematocrit was assessed just before CMR for quantification of extracellular volume fraction (ECV). Blood pressure was taken before and after CMR. Assessment of heart rhythm abnormalities was based on a 12-lead electrocardiogram (ECG) and an ambulatory electrocardiography monitoring for 24 h (Holter-ECG). Patients were also considered at risk of sudden death according to the Groh-criteria . FollowiThe group of patients was compared to 29 healthy subjects. The healthy population has been previously published , 12. The3) as well as a short axis (SAX) package  to cover the LV. Short axis stacks were planned and acquired always in the same ways.We applied CMR on a 1.5 T CMR Scanner  using a 32-channel surface coil. The scan protocol, as recently published , is giveFor myocardial tissue differentiation, parametric T1- and T2-mapping, fat/water-separated imaging and focal fibrosis imaging  were acquired. T2- and T1-mapping were performed in basal, medial and apical slices as described recently , 12.In short, motion-corrected T2-mapping was based on bSSFP gradient echo techniques  .Motion-corrected T1-mapping, based on modified look-locker inversion-recovery (MOLLI) , was perA multi-echo sequence was used for fat/water-separation  to detecFocal fibrosis imaging using LGE was performed in the same slice position as the cine imaging in 4CV, 3CV, 2CV and short axis  10–15 min after administration of contrast media. The protocol for the healthy control group was similar.42 version 5.3.2 .Image analysis was performed using cviShort axis cine images were used to determine LV volumes, mass and function by drawing endo- and epicardial contours (papillary muscles as part of the mass) at the end of the systolic and diastolic phases .Both, the values of T2 and T1 maps were quantified as previously reported . The quaThe quantitative analysis of mapping was performed as average value for slice and for each segment separately. The ROI was defined by the delineation of the endocardial and epicardial border of the myocardium. To ensure that blood or extramyocardial tissue are not included, safety rim of 5% was used. The segments were defined following the American Heart Association (AHA) segment model . The visThe detection of tiny fatty spots was possible applying fat/water separated imaging. Imaging was analyzed using pre-defined criteria . A suspep value < 0.05 was considered to indicate a statistically significant difference. Correlation analyses were performed using the Spearman rank correlation coefficients. For intra- and interobserver reproducibility. Images were analyzed twice by blinded readers.All results are shown as mean ± standard deviation. The statistical analysis was performed using SPSS® Statistics 23 . Normal distribution was analyzed graphically and with Kolmogorov-Smirnov test. For the comparisons of healthy volunteers to patients as well as within the FSHD1 group, we used an unpaired t-test and Mann–Whitney U test, respectively. A p = 0.253), LV mass Index (p = 0.211) as well as LV end-diastolic volume index (LVEDVi) (p = 0.192). . The three most frequent locations were the basal segments: inferolateral , LVEF  or LVEDVi (0.69 ± 0.13 ml/cm vs. 0.69 ± 0.09 ml/cm p = 0.991) , always located in the apical part of the interventricular septal wall Fig. , whereasThe medial and basal slices were analyzed. Reliability was high for both inter- and intra-observer evaluations . Apical segments were excluded due to the high exclusion rate (in 62% artifacts and/or inaccurate motion-correction).p = 0.159; medial: FSHD1 51.0 ± 2.8 ms vs. controls 49.8 ± 2.4 ms, p = 0.108).Basal and medial T2 maps of 52 patients were evaluated. 6/624 segments had to be excluded due to artifacts. T2 values did not differ between FSHD1 patients and the control group  50.4. ± 3.1 ms vs. LGE(−) 51.2 ± 2.8 ms, p = 0.391). There were also no gender differences within the FSHD1 group .T2 values did not differ between LGE-positive and LGE-negative FSHD1 patients  50.1 ± 2.2 ms vs. LGE(−) 50.0 ± 3.9 ms, p < 0.01) and the medial slices . Compared to healthy subjects, native myocardial T1 values were longer in segments with focal fibrosis . Interestingly, Native myocardial T1 values were also increased within the adjacent medial segments  , but also within the adjacent regions  . Medial: 979 ± 33 vs. 985 ± 23 ms, (p = 0.394). Global ECV was also similar: Basal (men: 23 ± 2.1% vs. women:25 ± 3.2% (p = 0.519)) and medial (men:24 ± 2% vs. women:25 ± 3.8% (p = 0.866)).There was no difference in global native T1 in the healthy control group between men and women. Native T1 in the basal slice: 978 ± 35 vs. 992 ± 18 ms  and the medial ECV  were slightly increased in females.The subtle effect of sex remained significant within the FSHD1 patient group. To avoid the impact of focal fibrosis on the results, we excluded basal segments  from our calculations and compared T1 values and ECV in the medial slice. Both, the medial T1 values , Holter in 43 (83%). Holter was not available in 3/17 patients with focal myocardial injury. Arrhythmic events were recorded in 10/43 (23%) FSHD1 patients. Non-sustained ventricular tachycardia was detected in one patient , premature ventricular beats > 1000 in 3/43, runs of supraventricular tachycardia (SVT) in 4/43  and intermittent low atrial rhythm in three patients. Ventricular arrhythmias were detectable in 4/7 patients (57%) with fat deposits and in 1/13 with focal fibrosis. SVT was evident in one patient with fat deposits and in one with focal fibrosis. The patient with non-sustained ventricular tachycardia had evidence of focal fibrosis and fat infiltration. There was only one patient with positive Groh-criteria  and normal CMR. T wave abnormalities could not be identified in any patient.In our FSHD1 population with preserved LVEF, we found myocardial tissue changes such as, focal fibrosis/LGE in 25% and focal fat infiltration in 13%. Diffuse subclinical fibrosis was detectable in segments adjacent to focal fibrosis probably indicating an ongoing process. Females seem to have slightly more diffused myocardial changes. Age was not different in patients with and without fibrosis. Heart rhythm abnormalities were detected also in patients with myocardial injury.Although we had excluded all patients with impaired LV systolic function, cardiac involvement in FSHD1 can be detected. Our findings support the case reports , 9, 21 dFocal fibrosis was predominantly located in the inferolateral region. This localization is not pathognomonic for NMD as it is also described in other cardiac diseases such as inflammatory disease, mitochondrial myopathy, MD 2 or Eosinophilic Granulomatosis with Polyangiitis , 22–24. Cardiac involvement in MD is well recognized in Duchenne muscle dystrophy (DMD) and Becker muscle dystrophy (BMD) and other muscular dystrophies with lamin A or C mutations. They are often associated with dilated cardiomyopathy and ventricular arrhythmias –28. ArrhWhereas the occurrence of arrhythmias and conduction abnormalities is well known in the case of dilated cardiomyopathy , the assPatients with different types of MD are known to suffer from supraventricular- and ventricular arrhythmias as well as high-degree conduction disturbances like atrioventricular blocks . AsymptoMyocardial fat infiltration is less studied, but due to recent technical developments the identification of small changes is less challenging , 20. PouParametric mapping is an innovative and reproducible method and brings unique quantitative diagnostic information about the myocardium. In the future, it may allow avoidance of contrast-media. In our study focal fibrosis as well as adjacent subtle diffuse fibrosis were detectable in a quarter of patients, using parametric mapping. Interestingly, we were able to identify differences between patients and healthy controls, but the absolute values in patients were still within the normal range. Our findings are underlining two aspects, first – quantitative mapping needs standardization and second it offers the chance to detect myocardial injury in a very early stage. Similar to our findings, Florian et al. showed in patients with different types of MD that ECV was able to detect subtle diffuse fibrosis in myocardial areas without focal fibrosis . SimilarSex and gender differences in different cardiac diseases are well known . It has In our study we could detect subtle sex and gender related differences in myocardial structure in FSHD1 patients compared to healthy subjects. These findings need further evaluation and confirmation. Interestingly, similar findings are described in other secondary cardiomyopathies. Cocker et al. identified in patients with viral myocarditis that males had a higher incidence of focal fibrosis, while women showed more often diffuse injury . The potAlthough cardiac abnormalities in FSHD1 patients are less recognized than in other MD, autopsy data reported myocardial fibrosis and focal fatty infiltrations. CMR allows the detection of myocardial tissue damage such as different types of fibrosis and fat already in the absence of functional abnormalities. Our findings in FSHD1 patients with preserved LVEF have to be elucidated in long-term follow-up studies. But it adds knowledge regarding the capability of CMR to detect myocardial injury in preserved LVEF.This is a single center cross-sectional study and the sample size of the matched groups is relatively small, but all of the subjects have a genetically confirmed diagnosis and all patients are well characterized in our department of neurology. In the view of the prevalence of the disease, it should be considered as representative.ECG as well as Holter-ECG was not available in all patients due to hyperaesthesia or logistic patient related reasons. Patients with arrhythmias that could influence the CMR scan quality were excluded from the study.The potential impact of the significant, but small differences in T1-mapping related values have to be elucidated in further long-term follow-up trials.We could not identify a relation between arrhythmia and native T1 mapping. But we have investigated only patients with preserved LVEF. One could expect that a larger sample size and an inclusion of all FSHD1 patients would lead to different results.The capability of prolonged monitoring and inclusion of all FSHD1 patients to influence clinical outcomes should be evaluated in following studies.Patients with FSHD1 and preserved LVEF show focal and diffuse myocardial injury. FSHD1 men have more often focal fibrosis, while in females diffuse myocardial changes seem to be more common. Myocardial fat infiltration is detectable as well. Further longitudinal multi-center trials are needed to investigate a potential relation between heart rhythm abnormalities and myocardial injury and its impact on long-term prognosis in FSHD1.


Background. Though several studies about prevalence, etiology, clinical characteristics, preceding events, clinical management, and outcome of Tako-Tsubo cardiomyopathy (TTC) exist, the current knowledge of TTC remains limited. Objective. In 2006, TTC was classified among the acquired forms of cardiomyopathy. On the basis of pathophysiological implications, we analyzed whether the presence of ST-segment elevation in lead -aVR  and the simultaneous absence of ST-segment elevation in lead V1 allow a reliable differentiation of TTC from acute anterior ST-segment elevation myocardial infarction (STEMI). A further investigative feature is the seasonal variation of TTC. Since acute cardiovascular events exhibit definite chronobiological patterns, various small studies have tried to evaluate whether this is also the case for TTC. Because results are conflicting, we also conducted a multicenter study and analyzed the findings in context with a systematic overview of available studies. Methods. We compared the ECG patterns of 115 patients with TTC, who were admitted to five large acute cardiac care centers associated with university hospitals in Southwestern Germany between January 2001 and June 2011, with those of 100 patients with acute anterior ST-segment elevation myocardial infarction (STEMI) treated in one of these centers. In addition, we performed a computer-assisted MEDLINE search of the literature from January 2000 to September 2011 and analyzed the chronobiological patterns of available TTC cases, including our TTC cohort. Results. Testing the predefined diagnostic criteria was superior to any other electrocardiographic finding and differentiated TTC from anterior STEMI with a sensitivity of 73%, a specificity of 84%, a positive predictive value of 63%, and a negative predictive value of 89%. Beyond that, the onset of TTC showed a clear variation as a function of season and month. While events occurred most frequently during summer , the event rate was the lowest in autumn (16.4%) and winter (21.9%). Chronobiological analyses on a monthly basis identified a significant annual rhythmic pattern in TTC, which peaked in August  and had its nadir in November (6.3%). Conclusions. Our data illustrate that the ST-segment changes in leads aVR and V1 represent a simple and accurate ECG criterion to differentiate TTC from anterior STEMI in patients who are admitted within 12 h of symptom onset. Similarly, the results of our seasonal analysis indicate a distinct chronobiological variation in TTC occurrence. TTC, thereby, differs from major acute cardiovascular diseases, especially acute myocardial infarction (AMI), which is characterized by winter peaks and troughs in summer. If these results are confirmed in large independent cohorts, they may yield diagnostic implications, changing the regular invasive AMI management in TTC patients. Tako-Tsubo cardiomyopathy (TTC), also known as stress cardiomyopathy, was first described in 1990 in Japan . TTC is To accomplish an optimal evaluation of the electrocardiographic segments, patients with bundle-branch block, left-ventricular hypertrophy, or atrial fibrillation and coronary artery disease requiring a percutaneous intervention were excluded. We performed the final analysis in a sub-cohort of 106 TTC and 85 STEMI patients, who were admitted within 12 h of symptom onset to five large acute cardiac care centers associated with university hospitals in Southwestern Germany between 2001 and 2011 for TTC and between 2009 and 2010 for anterior STEMI. The study was approved by the local ethics committees . All patients fulfilled the Mayo Clinic diagnosis criteria for TTC, which in particular include: (a) a transient left ventricular wall motion abnormality preferred in the midventricular and/or apical segments, which typically does not fit to a single coronary artery perfusion territory, (b) the absence of obstructive coronary artery disease or acute plaque rupture in the coronary angiography, though a coronary artery disease can coincidentally be presented, (c) new electrocardiographic changes, (d) at most, moderate elevation of cardiac ischemia markers, (e) a potential stressor , (f) exclusion of pheochromocytoma and myocarditis. All patients underwent coronary angiography to rule out CAD. The clinical variables were recorded in part prospectively (from July 2009). Twelve lead ECGs were recorded at a paper speed of 25 mm/s and amplification of 10 mm/mV. Deviations of the ST-segment from the baseline PR-segment were measured 80 ms after the J point and were considered significant when exceeding 0.5 mm in limb and 1.0 mm in precordial leads [To assess the seasonal pattern of TTC, we analyzed the chronobiological occurrence of our TTC cohort. The study was approved by the local ethics committees, and informed consent was obtained from all patients. Clinical variables were recorded retrospectively (from January 2001 to June 2009) and in part prospectively (from July 2009 to June 2011) on a standardized form. Retrospective data were actively searched in hospital discharge records and coronary care units as well as in cardiac catherization laboratory databases. The day of onset of symptoms was categorized both into one-month intervals and, for the analysis of seasonal variation, into three-month intervals divided in accordance to the more traditional astronomical seasonal definition, which most likely considers astrophysiological conditions and circumstances depending on earth’s rotation . Because of our limited cohort number, we additionally performed a computer-assisted MEDLINE search of the literature (from January 2000 to September 2011) using the following search terms: TTC, transient left ventricular apical ballooning syndrome, tako-tsubo-like left ventricular dysfunction, ampulla cardiomyopathy, tako-tsubo, and apical ballooning. The criteria for inclusion in our analyses were set a priori and included: (a) reporting of original data, (b) for the purpose of representativeness, inclusion of at least 30 cases, and (c) adherence to the requested diagnostic criteria for TTC. In the case of multiple publications describing an intersection of cases, we used the latest ones. The heterogeneity of the methodologies used among studies did not allow a formal meta-analysis; thus, data are presented in a narrative synthesis.p < 0.05. The study population was described in accordance with sociodemographic and clinical characteristics. Continuous variables are given as mean ± SD or medians (IQR). Categorial variables are expressed as percentages and numbers. Comparisons of continuous variables were analyzed by the t-test. The distribution of symptom onset within the three-month periods was tested for uniformity in the overall population by the chi-square test. Moreover, a chronobiological analysis of the seasonal patterns of TTC was performed by applying a partial Fourier analysis to the monthly data using validated Chronolab software.Statistical analyses were performed using SPSS Statistics version 14 and Microsoft Ecxel XP for Windows. Statistical significance was defined as two-sided p < 0.01), whereas the mean age of our anterior STEMI cohort was 64.3 ± 14.1 years with a majority of male patients (n = 73). The main complaints at admission did not differ from those of patients with acute myocardial infarction  and test types, e.g., high-sensitive versus conventional test were used at different times in different centers, the indicated means and medians were only partially comparable . While, p < 0.01), while STEMI of the anterior wall (p < 0.01). When testing the predefined diagnostic criteria, we found that the combined presence of ST-segment elevation in lead -aVR  and the absence of ST-segment elevation in lead V1 were superior to any other electrocardiographic finding and differentiated TTC from STEMI with a sensitivity of 73%, a specificity of 84%, a positive predictive value of 63%, and a negative predictive value of 89% , the event rate was the lowest in autumn (16.4%) and winter (21.9%). Chronobiological analyses on a monthly basis identified a significant annual rhythmic pattern in TTC, which peaked in August  and had its nadir in November (6.3%).We identified seven studies with data on seasonal and monthly variations, which reported a total of 537 cases including our TTC patients (n = 115). In this total population, the onset of TTC showed a clear variation as a function of season a and monTTC is a cardiac entity which, in its clinical features, clinical course, and outcome, is not easily distinguishable from acute myocardial infarction. Because symptoms are almost the same and it is associated with a substantial risk for adverse events, first diagnosis and acute treatment remain challenging. Female patients, especially postmenopausal women, are mostly affected ,14,15,16+-channel density is strongly decreased, the subepicardial myocytes cannot be hyperpolarized, and the adrenergic storm is manifested by moderate ST-segment elevations. These ECG characteristics may be useful in clinical practice to distinguish TTC from AMI.Since electrocardiographic changes of TTC patients are similar to those of patients with acute anterior STEMI, several reports analyzed the electrocardiographic pattern of both acute cardiac diseases to clarify their ECG characteristics but found limited ECG differentiation features ,29,30. CSeveral reports indicate a seasonal variation of TTC, which has its molecular origin in the chronobiological regulation of numerous known and suspected cardiovascular risk factors for the development of TTC, which are also of decisive importance for the chronobiological distribution of AMI. The different seasonal occurrence of both diseases may be explained by a different distribution of stressful situations, which should indeed happen by chance, since in both cardiac diseases a stimulation of the sympathetic adrenergic nervous system is suggested as the main pathomechanism. Our findings concerning the chronobiological pattern of TTC are in contrast with the seasonal distribution of AMI: in the second national registry of myocardial infarction (MI), a total of 259,891 cases of AMI were analyzed, and >50% more cases were reported during winter time than during the summer . Furtherp < 0.01), the event rate was the lowest in autumn (16.4%) and winter (21.9%). Chronobiological analyses on a monthly basis identified a significant annual rhythmic pattern in TTC, which peaked in August  and had its nadir in November (6.3%). AMI cases were reported mostly during winter time.Because the clinical features of TTC are similar to those of AMI and TTC is commonly associated with life-threatening complications, notwithstanding a completely recovery of the myocardial dysfunction, it is of decisive importance to establish criteria for the initial diagnosis and determine the appropriate treatment strategy. Therefore, it is of special interest to investigate accurate diagnostic criteria to distinguish TTC from the acute cardiac desease it mostly resembles, i.e., anterior STEMI. Our electrocardiographic analyses of the ST-segment shift both in TTC and in anterior STEMI patients indicated a simple and accurate differentiation criterion. The combined presence of ST-segment elevation in lead -aVR  and absence of ST-segment elevation in lead V1 were superior to any other electrocardiographic finding and differentiated TTC from STEMI with a sensitivity of 73%, a specificity of 84%, a positive predictive value of 63%, and a negative predictive value of 89%. The diagnostic accuracy was comparable with that of high-sensitivity (hs) troponin in a low-risk ACS group. Eventually, we suggest that the combination of the pre-defined ST changes in leads -aVR and V1 can be a useful criterion to differentiate TTC from anterior STEMI in patients who are hospitalized within 12 h of symptom onset. The results of our chronobiological analysis of TTC occurrence can also help to distinguish TTC from AMI. While TTC occurred most frequently during summer time (38.4%, Although our data are derived from past records and more clinical characteristics of TTC have been identified in recent studies, we suggest that each result should be interpreted as a part of a totality to understand the nature of a disease, which may require a long research effort. Presumably, if our results are confirmed in large independent cohorts, they may yield diagnostic implications, changing the regular invasive AMI management in TTC patients.


Neonatologists can use echocardiography for real-time assessment of the hemodynamic state of neonates to support clinical decision-making. There is a large body of evidence showing the shortcomings of conventional echocardiographic indices in neonates. Newer imaging modalities have evolved. Tissue Doppler imaging is a new technique that can provide measurements of myocardial movement and timing of myocardial events and may overcome some of the shortcomings of conventional techniques. The high time resolution and its ability to assess left and right cardiac function make tissue Doppler a favorable technique for assessing heart function in neonates. The aim of this review is to provide an up-to-date overview of tissue Doppler techniques for the assessment of cardiac function in the neonatal context, with focus on measurements from the atrioventricular (AV) plane. We discuss basic concepts, protocol for assessment, feasibility, and limitations, and we report reference values and give examples of its use in neonates. Conventional echocardiographic indices such as shortening fraction (SF) and ejection fraction (EF) have several shortcomings.There is an increasing body of literature on the use of TDI in neonates. The aim of this review is to provide an up-to-date overview of TDI techniques for assessment of cardiac function in the neonatal context, with a focus on measurements from the atrioventricular (AV) plane. We discuss basic concepts of TDI, protocol for assessment, feasibility and limitations, provide examples of its use in neonates and suggest directions for research and further exploration.8 Conventional measures of cardiac function generally assess changes in cavity dimensions and blood velocities rather than provide direct information on myocardial characteristics. Those include SF, EF and pulsed-wave Doppler measurements of blood flow. Several studies have demonstrated the relative lack of sensitivity of those measures in detecting myocardial dysfunction.7 EF can be calculated from SF,9 but as calculation of EF from SF is not feasible in hearts with asynchronous contraction and distorted geometry, newer guidelines recommend assessing the EF by Simpson biplane method.1The main task of the cardiovascular system is to provide the body with a sufficient supply of oxygenated blood to maintain adequate cellular metabolism. Cardiac output is determined by myocardial contractility, heart rate, preload, and afterload. No echocardiographic index of cardiac function can assess the contractility of the myocardium per se. Ambient loading conditions have an impact on all cardiac function indices.As most studies in neonates have used TDI to assess longitudinal motion of the AV-plane viewed from the apical position, this will be the acquisition modality discussed in this paper. When assuming a stationary position of the apex relative to the probe during the cardiac cycle, movement of the AV-plane will be the result of the average function of the myocardial wall between the apex and the AV-plane. TDI has the advantage of high time resolution (high frame-rate) and ability to assess both left and right cardiac function. Unlike deformation imaging by strain and strain rate indices, assessment of AV-plane motion does not offer regional myocardial function assessment. The lack of spatial resolution is, however, probably less relevant in neonates than in adults, in whom regional functional disturbances due to ischemia and scars are important aspects of cardiac function evaluation.The algorithms for assessing velocities of the myocardium are similar to the algorithms for assessing velocities of the blood. The ultrasound signals from blood and myocardium differ in two aspects; the signals reflected from myocardium are stronger (higher amplitudes) and the velocities are lower. The analysis software separates the signals from tissue and blood by these properties.There are two basic TDI techniques, pulsed-wave TDI (pwTDI) and color-coded TDI (cTDI). The user can use velocity–time curves by pwTDI Fig.  and cTDI10 and the curve usually shows the peak systolic and peak global displacement on each side of this notch  from the septal and left lateral wall for left ventricle assessment.17 subsequent studies often define the index by time intervals from TDI velocity curves.18 The MPI is the sum of isovolumic phases as a fraction of the ejection phase , also known as Tei index. Originally defined by time intervals from blood velocities,The velocity measurements of myocardium share many properties and limitations with measurements of blood velocities, including the Nyquist limit of velocity scale , limitations related to frame rate (time resolution) and angle dependency. Aliased velocity estimates occur when the muscle movement velocities are higher than the velocity scale. Figure 20 the outer edge of the curves will show higher velocities if the gain setting during recording is set high, but no studies to date have explored the effect systematically in neonates.To obtain pwTDI velocities, the echocardiographer place a sample area stationary in the ultrasound sector and obtain a spectral image showing the myocardial velocities from this region by time Fig. . Some ul22 ,24 the echocardiographer records the spectral curves. The velocities can be measured either on the machine directly or offline. It is customary to lower the gain of the spectral curve to remove out-of-band noise and then measure the values at the peak of the curve band  has higher impact on frame-rate than sector depth. The user can increase frame-rate in a fixed-sized sector by reducing the beam density and hence reduce the lateral resolution. The output shows a color-coded velocity sector super-imposed on a gray-scale image with low frame-rate, similar to Doppler color flow mapping of blood. At a cTDI frame-rate of 200 Hz and using a probe transmitting at 5 MHz and a velocity scale of ±0.16 m/s, the cTDI sector will typically contain 40 beams, and if the echocardiographer increases the frame-rate to 400 Hz, the sector will typically contain 20 beams. During off-line analyses, the software displays velocities from sample areas within the cTDI sector as velocity–time curves, similar to pwTDI velocities. Importantly, the curve will show the average velocity from all pixels within the sample area, more resembling a curve within the middle of the pwTDI band than the edge of the band usually assessed by pwTDI. cTDI measurements enables a more extensive use of spatial averaging than pwTDI. The echocardiographer can adjust the level of averaging between adjacent pixels laterally and radially in the cTDI sector during recording and the analyzer can adjust the length and width of the sample area during analysis. Averaging will cause spatial smoothing due to more velocities being used in the measurements, but at the risk of including pixels with false velocities from stationary echoes (pericardium and stationary artefacts), fast-moving structures , and velocities from areas other than the AV plane. In contrast to pwTDI, cTDI enables use of time-based averaging, both within a heartbeat by averaging consecutive velocity measurements and between heartbeats by averaging velocities assessed at the same time point in consecutive cardiac cycles. Averaging between consecutive heartbeats requires correct identification of the onset of heartbeats. Deformation imaging guidelines in adults recommend using the peak of the QRS complex as start of systole.29 In addition to the averaging techniques applicable to cTDI velocity measurement, drift compensation is an additional averaging principle for cTDI displacement assessment.cTDI requires a more comprehensive post-processing analysis to obtain measurements compared to pwTDI, but it has the advantage of the ability to assess the velocities from several areas simultaneously and more easily avoid areas with artefacts and poor image quality. cTDI enables stationary sample areas in the ultrasound sector or non-stationary sample areas within the sector to sample the tissue velocities from the AV valve plane throughout the cardiac cycle. Non-stationary sample areas improve repeatability and show velocity measurements different from stationary sample areas in adults.27 The differences increase if large amounts of gain are applied to the pwTDI curves.27 pwTDI was introduced before cTDI, and more studies have used pwTDI than cTDI in adults and in neonates. Velocities by cTDI more closely resemble the true velocities in experimental settings.26 pwTDI velocities from within-the-band show better agreement against cTDI velocities than pwTDI velocities from the outer edge of the band.31 Similarly, displacements by integration of within-band pwTDI velocities show better agreement toward displacement by cTDI velocities and toward excursion by M-mode than integration of velocities from the outer edge of the band, both in phantom models and in-vivo analyses.31The differences between pwTDI and cTDI prevent the measurements from being interchangeable. cTDI enables the visualization of multiple heart segments from one single view and measures mean systolic and diastolic velocities (rather than peak as is the case for pwTDI). As a result, velocities obtained using cTDI are generally 20% lower in systole and diastole compared to pwTDI. The two methods are therefore not interchangeable.27 and could therefore remove differences between the pathophysiological and normal clinical states. Studies report different indices for repeatability, with their strengths and weaknesses, and the user must interpret repeatability indices in relation to the population studied.Most repeatability indices assess random variation. Repeatability will therefore be better in analysis of images with large amount of averaging applied. However, averaging will tend to lower peak velocity measurements16 the latter more resembling a test–retest situation. Typical coefficient of variation (COV) values range have been reported as 30–60% for isovolumic acceleration and 5–20% for cTDI velocities, displacements and time intervals,12 while authors report COVs as low as 4–8 % for pwTD velocities.32Few studies in neonates report test–retest repeatability. Most neonatal studies have assessed pwTDI repeatability by repeated assessment of velocity peaks and time intervals using the same spectral curve. cTDI recordings often show worse repeatability than re-assessment of pwTDI spectral curves, because cTDI repeatability tests usually includes position of a new sample area,33 Vendors have put much effort into standardizing measurements and inter-vendor variation was probably a more significant obstacle in the past. Authors have found good agreement for measurements between vendors in a recent study26 while earlier studies have found systematic differences between vendors for pwTDI34 and cTDI35 measurements, with bias up to 25% and 15%, respectively.Inter-vendor variation has gained much attention for newer imaging modalities, but the inter-vendor agreement for tissue Doppler indices seems better than for conventional measurements of blood velocities and dimensions.37 To compare between hearts of different sizes, the neonatologist can normalize measurements for cardiac size. Neonatal studies have often used end-diastolic septal length or length from apex to the lateral AV-plane hinge for normalization for size39 and reported velocities and excursions normalized by LV length in neonates and children.40 Others have suggested normalizing by dividing the velocities by the end-diastolic diameter of the LV.19 By using the end-diastolic ventricle length as a measure for cardiac size, peak systolic velocity (s′) adjusted for cardiac size  will express the peak systolic strain rate for the region between apex and the AV-valve plane, and, similarly, displacement adjusted for cardiac size will express the peak strain for the region. We therefore suggest end-diastolic length of the ventricle wall as the most suitable index for normalization for size, assessed between the echo from the pericardium at the apex and the septal hinge of the mitral wall.In general, large peak systolic AV-plane velocities, accelerations, and displacements imply better myocardial function. This can be a result of better contractility or favorable loading conditions. Large hearts have higher velocities and displacements than small hearts.41 As loading conditions have less impact on peak systolic strain rate than peak systolic strain,8 loading conditions possibly have less impact on systolic velocities than on displacements. Changes in peak systolic velocities (when adjusted for heart size or compared between hearts of similar size) can imply changes in contractility, but importantly, the neonatologist must consider the loading condition when interpreting the values. Higher diastolic velocities can imply better myocardial relaxing function, but interpretation of diastolic velocities is more challenging because more factors influence the measurement. Restoring forces from the systolic contraction, active relaxation (diastolic function), load (venous pressure), and atrial contraction could influence diastolic velocity measurements.Preload and afterload have impact on systolic velocities and deformation indices.38 and others by reporting one diastolic peak in case of fusion and two peaks if two diastolic peaks could be separated.12In neonates, the e′ and a′ peaks tend to fuse at higher heart rates. The a′ is the peak during atrial systole. If the atrial systole occurs shortly after the onset of diastole, the a′ velocity wave could “climb” on top of the e′. The velocity curve could then show only one diastolic peak, as shown in the two last cardiac cycles in the upper panel of Fig. 43 In adults with heart failure with preserved ejection fraction, E/e′ is used as an index of diastolic heart function.15 A large E/e′ could indicate a high filling pressure and poor diastolic function. Guidelines in adults recommend use of pwTDI rather than cTDI velocities in estimation of E/e′ because the tissue Doppler velocities vary between the modalities and more validation studies have used pwTDI than cTDI.15 Its role as a function index in neonates awaits further clarification.The peak E mitral blood flow velocity divided by peak e′ tissue Doppler velocity (E/e′) has been assessed in neonates.17 by use of the time intervals from blood-Doppler velocity curves. Although studies have found significant associations between MPI and several pathological states, authors have questioned the use of MPI as an index of contractility, finding the index highly dependent on load and even questioned its ability to assess changes in contractility.44 Several studies have reported MPI by tissue Doppler in neonates.47 A low value might reflect a better cardiac function than a high value, but the neonatologist must consider loading conditions when interpreting MPI, as MPI increases with increased afterload and with reduced preload. Its use in neonates awaits further clarification. Neonatal studies have also assessed the isovolumic time intervals.48 Short isovolumic phases generally imply better cardiac function, but several factors influence time interval measurements and make their use as cardiac function indices challenging. The time interval from onset of QRS to peak s′ velocity has in experimental settings been regarded as an index of maturation of the electromechanical coupling, with a short time interval showing a more mature coupling, thus implying a better cardiac function. Recently, Kahr and colleagues showed that the time interval decreases with postnatal age in neonates.19Indices based on time intervals are independent of heart size and the angle of insonation, making comparisons between different heart sizes and during growth easier. The first publication of MPI (Tei index) proposed this index as a relatively load-independent measure of contractilityTable 49 The sector should be narrow and shallow to keep the frame-rate high, but it must show the relevant structures throughout the cardiac cycle. Acquisition of several cardiac cycles will enable direct comparisons between heartbeats and is a prerequisite for averaging between heartbeats.In the cTDI analyses, frame-rate will have impact on the time resolution of measurements. A high frame-rate will reduce the risk of missing true peak values between frames. A small sector, especially a narrow sector, will enable high frame-rates while maintaining a good lateral spatial resolution. If a larger sector is used, it is possible to obtain movement from right, septal, and left hinge points of the AV plane in a single recording. This reduces the burden of repeated image acquisition and enables the assessment of left- and right-cardiac function from the same image. However, a large sector will reduce the time resolution (frame-rate), the lateral spatial resolution (few beams in the sector), or both. The frame-rate requirements are probably more critical for short-time intervals and for diastolic velocities than for long-time intervals, systolic velocities, and displacements.28 The pwTDI gain should be low to avoid overestimating pwTDI velocities. For obtaining the cTDI curves during off-line analysis, studies have used different sizes for the sample area. We suggest a sample area of 2 × 2 mm in premature and 3 × 3 mm in term neonates. The analyses should use averaging techniques with caution, especially for short timing intervals and diastolic peaks. Studies should describe in detail the use of averaging and neonatologists should use similar averaging settings for longitudinal assessment in clinical practice. Between-beat averaging techniques require regular rhythm and proper ECG recordings to ensure that the user uses the same start point for each heartbeat. Tracing of the cTDI sample area to keep it at the AV hinge during the cardiac cycle has impact on the measurements and repeatability in adults29 but no study has yet systematically explored the difference between measurements from traced and stationary sample areas in neonates.We suggest defining onset of systole at the peak of the QRS complex, in accordance with deformation imaging guidelines in adults.The systolic peak is the peak during the ejection phase. The peak in the left lateral wall occurs earlier in the ejection phase than the septal and right lateral peaks. If there are two distinct diastolic peaks in the filling phase and the velocity curve shows low velocities in mid-diastole, the peaks should be assessed as the e′ and a′ velocities. With an increasing degree of fusion, the interpretation of the two peaks as separate values becomes more difficult. If two diastolic peaks can be clearly identified, the first peak could probably be regarded as an e′. By increased degree of fusion, e′-velocities will have more impact on the second peak (the a′-wave will climb on top of the e′-wave) and interpretation of the second peak as a function index becomes more challenging. In case of complete fusion, the velocity curve will show only one diastolic peak. The a′-wave occurs simultaneously with the P-wave on the ECG-recording, while the isovolumic contraction occurs simultaneously with the QRS-wave. In cases of complete fusion of e′ and a′, the operator could therefore use the ECG signal to avoid interpreting the negative peak in the isovolumic contraction Fig.  as an a-In the isovolumic contraction phase, the peak velocity is usually positive  or by electrical properties (peak of the QRS complex). This will have an impact on the measurements and we recommend defining onset of systole at the peak of the QRS complex to standardize measurements. If the peak of the QRS complex defines the onset of systole, there will be an early-systolic displacement away from the probe  before onset of mechanical movement towards the apex. When applying between-beat averaging or drift compensation for cTDI displacement analyses, it is important to ensure that the curves for each heartbeat start at the same point in the cardiac cycle and that the cardiac rhythm is regular. The closure of the aortic valve causes a notch in the displacement curves, especially for the left lateral and septal walls Fig. . Peak sy14 . Yates and colleagues found worse left MPI and left and right E/e′ in BPD neonates but similar tissue Doppler velocities and right MPI compared to controls.62 Sehgal and colleagues found worse RV peak systolic and isovolumic velocities and E/e′ and MPI compared to premature controls at 36 weeks, and that E/e′ was associated with duration of subsequent respiratory support.43 Czernic and colleagues found similar initial right side MPI in premature neonates with and without subsequent development of BPD, and that MPI remained high in those developing BPD.47 Recently, Yajamanyam and colleagues found worse right, septal, and left MPI, higher right s′ velocity and right isovolumic relaxation time in premature neonates with severe and with mild BPD compared to premature neonates with no BPD, while the other tissue Doppler velocities were similar between groups.63 The latter study could indicate a compensatory increase in right cardiac contractility to overcome worse right cardiac afterload. Acute changes in load occur in closure of a patent ductus arteriosus (PDA). El-Khuffash and colleagues showed worse left, septal, and right tissue Doppler velocities 1 and 18 h after surgical closure of a PDA and higher (worse) time indices from the left lateral wall at both time points.64 Parikh and colleagues found worse left and right tissue Doppler velocities and MPI in premature neonates with hemodynamically significant PDA, and patients whose PDA remained open despite indomethacin had worse velocities and MPI compared to those with successful closure by indomethacin.65 Several studies have assessed tissue Doppler velocities and time intervals in neonates born small for gestational age.68 These show differences in tissue Doppler velocities and MPI not detected by conventional indices of cardiac function.Tissue Doppler indices from apical four-chamber views often show differences between healthy and sick neonates. Observational studies comparing tissue Doppler indices against conventional indices often show better discriminating capabilities. Vitali and colleagues showed that surfactant administration to premature neonates with respiratory distress syndrome improved right cardiac systolic velocities 2 h after the procedure.Use of indices derived from tissue Doppler velocity–time curves in neonates is feasible. They detect differences between neonates in normal and pathological conditions not diagnosed by conventional indices. Systolic velocities and displacements are well-established indices of cardiac function in neonates, while interpretation of tissue Doppler time intervals and diastolic velocities as markers of cardiac function is more challenging. Standardization of acquisition and interpretation of indices will facilitate its use as a bedside tool in neonatal intensive care. Although less dependent on loading conditions than conventional indices, these new indices cannot assess the contractility per se. The neonatologist must take loading conditions and the interplay between the right and left side into account when interpreting measurements. In general, high preload and low afterload are associated with higher velocity and acceleration indices and shorter time intervals. As for most diagnostic tools, studies have not yet shown that medical interventions based on abnormal TDI measurements lead to improvements in patient outcomes. Interventions should be based on evaluation of the combination of clinical state and available cardiac function indices, and not be solely based on one parameter. Further research steps should focus on exploring the impact of pathophysiologic processes in neonatal hearts on these new indices, especially on how and when to apply therapeutic interventions guided by tissue Doppler indices. In the interim, we recommend that, when feasible, tissue Doppler indices of velocity and event timings should form part of a routine functional echocardiogram in the neonatal population.