In the multivariate logistic regression analyses, TAPSE was an independent factor associated with anaerobic threshold and peak oxygen consumption (p < 0.05 for both). Conclusions: Right ventricular impairment was associated with reduced exercise capacity in patients with chronic heart failure. Such knowledge would be useful to estimate patients’ exercise capacity and prescribe cardiac rehabilitation. Its longitudinal association and clinical implication need further studies.Background: The association between right ventricular function and exercise capacity in patients with chronic heart failure remains uncertain. Several studies very recently mentioned the association between right ventricular reserve and exercise capacity, whereas the implication of tricuspid annular plane systolic excursion (TAPSE) remains uninvestigated. We aimed to assess the impact of TAPSE on exercise capacity in cardiac rehabilitation candidates. Methods: Data from patients with chronic heart failure who received cardiopulmonary exercise tests and transthoracic echocardiography prior to cardiac rehabilitation were retrospectively collected, and their association was investigated. Results: A total of 169 patients with chronic heart failure  were included. Tertiled tricuspid annular plane systolic excursion significantly stratified anaerobic threshold (10.2 ± 2.2, 11.4 ± 2.2, and 12.2 ± 2.8 mm;  Exercise capacity has been a matter of great concern thus far given that it is considerably associated with mortality and morbidity in patients with heart failure. Exercise capacity is predominantly affected by the amount of skeletal muscle in patients with heart failure, whereas the impact of cardiac function on exercise capacity might be partial .Nevertheless, impaired right heart function was recently demonstrated to be associated with reduced exercise capacity in patients with coronary artery disease , whereasTheoretically, systolic right heart failure would decrease forward flow toward pulmonary vasculature and impairs oxygen exchange. Diastolic right heart failure would exacerbate systemic congestion and impair peripheral circulation. Both of these would worsen exercise capacity. A further concern is whether cardiac rehabilitation can improve exercise capacity, particularly for those with impaired right ventricular function.Very recently, the association between right ventricular function/reserve and exercise capacity has been investigated among various types of cohorts, including hospitalized heart failure patients, systolic heart failure patients, and diastolic heart failure patients ,4,5,6. TIn this study, we investigated the association between right ventricular function assessed using echocardiography and exercise capacity quantified by cardiopulmonary exercise tests in patients with chronic heart failure prior to cardiac rehabilitation. We also investigated the impact of baseline right ventricular function on the effect of cardiac rehabilitation. Consecutive patients with chronic heart failure who received cardiac rehabilitation between 2015 and 2020 at our institute were considered for inclusion in this retrospective study. Patients with active angina pectoris, those with a history of acute coronary syndrome within the past 3 months, those with unstable hemodynamics, those with symptomatic congestion, those with critical arrhythmia, those with active systemic infection, or those unable to participate in cardiac rehabilitation due to various other comorbidities did not receive cardiac rehabilitation and were excluded from this study. The diagnosis of heart failure was made according to the Framingham criteria. Patients who received cardiopulmonary exercise tests and transthoracic echocardiography within one week before cardiac rehabilitation were finally included for the present analysis. The institutional review board approved the study protocol. All participants gave written informed consent beforehand.A symptom-limited cardiopulmonary exercise test was performed using a bicycle ergometer with a ventilator and expired gas analyzer , according to the American Heart Association’s guidelines . All patContinuous data of oxygen consumption (VO2), production of carbon dioxide (VCO2), and minute ventilation (VE) were measured during the tests on a breath-by-breath basis. Peak VO2 (PVO2) was defined as the highest VO2 noted during the exercise. Anaerobic threshold (AT) was determined using the V-slope, ventilator equivalents, and end-tidal pressure methods by the attending experts . Considering the Borg scale, which indicates patients’ objective fatigue in the range of 6–20, a score above 17 was targeted to terminate the tests. The respiratory exchange ratio was targeted at above 1.10.Transthoracic echocardiography was performed according to the American Society of Echocardiography guidelines . Right vThe peak early diastolic transmitral flow velocity (E) was measured by pulse wave Doppler echocardiography. Tissue Doppler measurement of mitral annular velocity (e’) at the left ventricular lateral wall was also measured. E/e’ was calculated as an index of diastolic function. LV end-diastolic diameter (LVDd) was measured through parasternal long-axis views at mitral tip level. Left ventricular ejection fraction was calculated using the modified Simpson’s method using 2- and 4-chamber views or using the Teichholz method from the M-mode image.Cardiac rehabilitation was performed in a standard manner according to the Japanese Circulation Society guidelines . For exet-tests. A value of p < 0.05 was considered statistically significant. Statistical analyses were performed using JMP® 12 .Continuous variables were expressed as the mean and standard deviation. Categorical variables were expressed as numbers and percentages. The association between clinical parameters including TAPSE and exercise capacity data including AT and PVO2 were investigated using linear regression analyses. Variables significant in the univariable analysis were included in the multivariable analysis with the forced entry method. Variables tertiled by TAPSE were compared using one-way analysis of variance and multiple comparisons with Tukey methods. Among patients who received 5-month cardiac rehabilitation, changes in AT and PVO2 following cardiac rehabilitation were assessed in those with normal TAPSE  and in those with abnormally low TAPSE ≤ 16 mm separately using paired Among 345 patients, a total of 169 patients with chronic heart failure  were finally included . Most ofBaseline characteristics were tertiled by TAPSE in p < 0.05 for both; p < 0.01; In the univariable analyses, several clinical variables including echocardiographic parameters were significantly associated with the AT level. TAPSE was independently associated with the AT level when adjusted for variables significant in the univariable analyses, as well as age and NYHA class . Both AT and PVO2 remained high following cardiac rehabilitation in patients with normal TAPSE (p > 0.05 for both; p < 0.05; Following 5-month cardiac rehabilitation, both AT and PVO2 improved significantly (from 11.3 ± 2.2 to 12.2 ± 2.5 mL/min/kg for AT and from 17.5 ± 4.7 to 19.7 ± 4.9 mL/min/kg for PVO2, In this study, we investigated the association between right ventricular function quantified by TAPSE and exercise capacity quantified by AT and PVO2 in patients with chronic heart failure. The major findings are as follows. Firstly, impaired right ventricular function represented by lower TAPSE was independently associated with reduced exercise capacity indicated by lower AT and PVO2, respectively. Secondly, exercise capacity remained high in patients with preserved baseline TAPSE, whereas an improvement in exercise capacity was observed following 5-month cardiac rehabilitation in patients with low baseline TAPSE. Various factors are associated with exercise capacity in patients with chronic heart failure, but there is a scarcity of studies investigating the impact of right ventricular function on exercise capacity thus far ,11. ElevIncremental pulmonary artery pressure during exercise is a significant afterload on the right ventricle . ImpaireA low TAPSE also indicates diastolic dysfunction of the right ventricle, accompanying systemic congestion. Akiyama and colleagues demonstrated a parallel improvement in systemic congestion and TAPSE despite unchanged left ventricular end-diastolic volume and cardiac output during hospitalization for acute heart failure . BorlaugGhio and colleagues reported that impaired right heart function was a prognostic risk factor independent of pulmonary hypertension in patients with chronic heart failure . Other iFortunately, patients with low TAPSE, i.e., impaired right ventricular function, could also enjoy improvement in exercise capacity following cardiac rehabilitation, as shown in the present study. Cardiac rehabilitation has multidisciplinary effects in improving exercise capacity and prognosis in patients with chronic heart failure. Cardiac rehabilitation might have a direct effect in improving skeletal muscle and exercise capacity ,17. ImprFurther studies are warranted to propose a specific protocol for cardiac rehabilitation for those with low TAPSE at baseline. Cardiac rehabilitation is essential also for those with normal TAPSE at baseline to maintain their exercise capacity, given the progressive nature of chronic heart failure.We cannot ignore that there are several limitations. First, this is a retrospective study using a moderate sample size cohort. Cardiac rehabilitation was not continued completely for all outpatients. We performed multivariable analyses, but any other uninvestigated confounders might exist. Second, we used TAPSE as a representative of right ventricular function. There are several other parameters associated with right ventricular function, including three-dimensional right ventricular ejection fraction and right ventricular strain analyses. However, TAPSE is easy to measure without any requirement of whole right heart images and expert techniques. Third, exercise-induced pulmonary hypertension is one of the dominant determinants of impaired exercise capacity. Incremental afterload on the right ventricle during exercise increases transverse contraction and reduces longitudinal shortening . TAPSE iRight ventricular impairment was associated with reduced exercise capacity in patients with chronic heart failure. This knowledge would be useful to estimate patients’ exercise capacity and prescribe cardiac rehabilitation. Its longitudinal association and clinical implications remain concerns for the future.


The presence of right ventricular (RV) dysfunction in imaging is more efficient in acute PTE risk evaluation.Accurate risk stratification is the most important step in the management of patients with acute pulmonary thromboembolism (PTE). Pulmonary embolism severity index (PESI) is a clinical tool for PTE risk stratification. CHA2DS2‐VASc and PESI score and each of them with RV dysfunction on computed tomography pulmonary angiography (CTPA).This study aims to evaluate the association between CHA2DS2‐VASc and PESI scores were calculated for all of them. RV dysfunction including an increase in RV to left ventricular diameter ratio, interventricular septal bowing, and reflux of contrast medium into the inferior vena cava was examined by CTPA.One hundred eighteen patients with a definite diagnosis of PTE were entered. The CHA2DS2‐VASc scores were significantly associated with RV dysfunction. In addition, different classes of PESI scores were correlated with RV dysfunction. Moreover, this study showed that the CHA2DS2‐VASc score and PESI score had a positive correlation. The area under the curve value for the CHA2DS2‐VASc score was 0.625 with 61.54% sensitivity and 60.0% specificity for predicting RV dysfunction while for PESI score was 0.635 with 66.7% sensitivity and 60.0% specificity.PESI and CHA2DS2‐VASc and PESI scores are positively correlated, but they are both associated with RV dysfunction diagnosed by CTPA. CHA2DS2‐VASc and PESI scores are able to predict RV dysfunction.This study showed that not only CHA The CHA2DS2‐VASc score has been considered for predicting the prognosis and mortality of coronary artery bypass grafting surgery and various cardiovascular diseases such as acute myocardial infarction and heart failure.2DS2‐VASc score is associated with cardiovascular events such as ischemic stroke, thromboembolism, and death in patients without atrial fibrillation.2DS2‐VASc score has been suggested to provide further prognostic information besides the PESI score.2DS2‐VASc score and echocardiographic indices of RV dysfunction in patients with acute PTE.2DS2‐VASc score with the PESI score, association and predictive values of PESI score and CHA2DS2‐VASc for RV dysfunction on CTPA and assessed the correlation between different variables of these two scores and RV dysfunction.The pulmonary embolism severity index (PESI) specifies 11 features from history, demographics, and clinical findings and is a clinical risk stratification tool. Some studies suggest the association between the presence of RV dysfunction and PESI in patients diagnosed with PTE.2This was a retrospective study that was conducted on patients over 18 years of age with a diagnosis of acute PTE by CTPA during the period between January 2019 and December 2020. Exclusion criteria were a history of previous thromboembolism, use of thrombolytic and anticoagulant agents, a history of the previous diagnosis of RV dysfunction, the presence of intracardiac lesions, and any concomitant disorder affecting the hemodynamics of the patient . As a result, 118 eligible patients were included in the study consecutively after signing the written informed consent. The study was approved by the ethics committee of the Shahid Beheshti University of Medical Sciences (Ethics code: IR.SBMU.RETECH.REC.1400.179).All CT scan images were acquired using a 16‐section multidetector CT scanner based on the standard CTPA protocol for PTE and 20 s after injection of 100 ml contrast media at a rate of 5 ml/s. Careful evaluation of the CTPA images was made by an expert radiologist to detect signs of RV dysfunction by analyzing RV/LV diameter ratio, interventricular septal bowing and reflux of contrast medium into the IVC. LV and RV dimensions were measured exactly below the atrioventricular leaflets and defined as the distance between the endocardium of the septum with the ventricular wall. Reflux of contrast medium was considered noticeable only when the reflux was seen into the IVC and hepatic veins. Diagnosis of RV dysfunction was based on the presence of at least one of these three criteria: (1) RV/LV diameter ratio ≥0.9; (2) bowing of interventricular septum; and (3) reflux of contrast medium into the IVC.2DS2‐VASc, blinded to patient outcomes. PESI score includes 11 features and is calculated by summing the patient's age in years (age > 80 years) and point assigned for each of the 10 variables as follows: 10 points for the male gender, 30 points for a history of malignancy, 10 points for a history of heart failure, 10 points for a history of chronic lung disease, 20 points for the presence of tachycardia (heart rate >109 beats/min), 30 points for systolic hypotension (systolic blood pressure <100 mmHg), 20 points for the presence of tachypnea (respiratory rate ≥30 breaths/min), 20 points for a temperature less than 36°C, 60 points for an altered mental status, and 20 points for arterial oxygen saturation less than 90%. According to the PESI score, patients were categorized into five classes including Class I (<65 points: very low risk), Class II (66–85 points: low risk), Class III (86–105 points: intermediate risk), Class IV (106–125 points: high risk), and Class V (>125 points: very high risk).A clinician reviewed charts and scored PESI and CHA2DS2‐VASc score was calculated for each patient as follows: 1 point for each of congestive heart failure, systemic hypertension, age between 65 and 74 years, diabetes mellitus, vascular disease, and female gender and 2 points for each of age equal or more than 75 years and history of the previous stroke, transient ischemic attack, or thromboembolism.The CHASD or quartiles were used for the analyses of parametric variables. Frequency and percentage were used to represent categorical variables. Kolmogorov–Smirnov statistics was used for checking the normal distribution assumption of continuous variables. In addition, simple linear logistic and logistic regression were used to perform the analyses. Independent samples t‐test was used for variables with normal distribution and Mann–Whitney U test was used to assess in absence of normal distribution. Odds ratio (OR) was reported for the effective variables. To evaluate CHA2DS2‐VASc and PESI scores accuracy at predicting RV dysfunction, we used the receiver operating curve (ROC) analysis by MedCalc. ROC curve data were reported as the area under the curve (AUC). p < .05 was considered as the statistical significance level.All statistical analyses were performed using the SPSS software, version 23 (SPSS Inc.). The mean ± 3SD of 59.64 ± 20.6 years. The calculated PESI score was ranged from 27 to 283 with a mean ± SD of 106.5 ± 46.9. The prevalence of PESI score risk factors among patients showed that male gender, arterial O2 saturation of less than 90%, and heart rate more than 109 beats/min were the most prevalent risk factors  males and 58 (49.2%) females were entered. The patients aged from 18 to 93 years old with a mean ± 2DS2‐VASc score in groups with and without RV dysfunction was evaluated and showed that both scores were significantly higher in patients with RV dysfunction. There was a statistically significant association between RV dysfunction and PESI score and also, CHA2DS2‐VASc score . Among RV dysfunction criteria, PESI score and CHA2DS2‐VASc score were correlated with reflux of contrast medium into the IVC   had RV dysfunction and 40 (33.9%) did not have RV dysfunction. Among the patients with RV dysfunction, 57 cases (48.3%) were in terms of reflux of contrast medium into the IVC, 56 cases (47.5%) were in terms of RV/LV diameter ratio ≥0.9 and 28 cases (23.7%) were in terms of interventricular septal bowing (Table The distribution of PESI score among patients with classification into five classes is shown in Table 2DS2‐VASc score and the PESI score was measured and demonstrated a positive correlation with r = .523 (p < .0001). Results of the ROC analysis showed CHA2DS2‐VASc score had the AUC value of 0.625  for predicting RV dysfunction with 61.54% sensitivity and 60.0% specificity (p = .020). The AUC value of PESI score for predicting RV dysfunction was found to be 0.635  with sensitivity of 66.7% and specificity of 60.0% (p = 0.018)  Table .42DS2‐VASc and PESI scores are correlated with RV dysfunction. Onuk et al. concluded that the CHA2DS2‐VASc score can be used as a risk stratification and prognostic tool in the context of acute PTE, besides the PESI score.2DS2‐VASc score can predict prognosis and management of acute PTE patients.2DS2‐VASc score as an independent predictor of the RV dysfunction in patients with acute PTE with an AUC of 0.621, 70% sensitivity and 50% specificity.2DS2‐VASc score had the AUC of 0.625 for predicting RV dysfunction with 61.54% sensitivity and 60.0% specificity. Although Gok et al. assessed RV dysfunction using echocardiography this study aimed to assess RV dysfunction by CTPA.This study aimed to demonstrate that CHAWe also analyzed the predictive value of the PESI score for RV dysfunction which demonstrated an AUC of 0.635 with a sensitivity of 66.7% and specificity of 60.0%. Our study showed that higher classes of PESI score were associated with RV dysfunction, meaning that patients without RV dysfunction are seen in Class I more than patients with RV dysfunction, and patients with RV dysfunction are seen in higher classes of PESI score. Cho et al. conducted a study on 229 patients with acute PTE and divided the patients into two groups based on RV/LV diameter ratio. RV/LV diameter ratio >1 group showed significantly more patients with simplified PESI (sPESI) score of 2 and 3 in contrast to the RV/LV diameter ratio <1 group and score of 4 and 5 was only seen in the group with RV/LV diameter ratio >12DS2‐VASc score was only correlated with the reflux of contrast medium into the IVC. Shayganfar et al. suggested that the CTPA indices including the presence of reflux of contrast medium into the IVC and the presence of an abnormal interventricular septal morphology as indicators of high PESI score but they did not find any association between RV/LV diameter ratio and PESI score.2DS2‐VASc score, as well.Different studies showed that the presence of RV dysfunction alone in the context of acute PTE is sufficient for the purposes of risk stratification and adverse outcome.Aviram et al. evaluated CTPA parameters among the patients with acute PTE and showed that increased RV/LV diameter ratio was more common and also, only substantial grades of reflux of contrast medium into the IVC was related to 30‐day mortality.2DS2‐VASc score and PESI score have a positive correlation with r = .523 (p < .0001), which was not assessed to date, as far as we are concerned. It is plausible that a number of limitations may have influenced the results obtained. This is a retrospective, observational, and single‐center study with a limited number of patients. Inevitably, a retrospective study design has its own limitations which makes it susceptible to multiple biases. However, we attempted to limit these biases by defining a time frame from which vital signs could be used for scoring. Apart from that, since our data is based on only a single time point, it may not reflect the patient status over long periods. Another possible source of error may be due to the participation of only one radiologist for reading the CTPA and one observer calculating the scores and more observers might have increased the validity of our study. We hope further studies will draw definite conclusions.In addition, in this study, we showed that CHA52DS2‐VASc and PESI scores are positively correlated, but also they are both associated with RV dysfunction diagnosed by CTPA. CHA2DS2‐VASc and PESI scores are able to predict RV dysfunction and are associated with reflux of contrast medium into the IVC among RV dysfunction criteria on CTPA. Further studies are required to define the role of the CHA2DS2‐VASc score in acute PTE risk stratification.This study showed that not only CHAThe authors declare no conflict of interest.Supporting information.Click here for additional data file.


Background: Right ventricular (RV) function plays a vital role in the prognosis of patients with chronic thromboembolic pulmonary hypertension (CTEPH). We used new machine learning (ML)-based fully automated software to quantify RV function using three-dimensional echocardiography (3DE) to predict adverse clinical outcomes in CTEPH patients.Methods: A total of 151 consecutive CTEPH patients were registered in this prospective study between April 2015 and July 2019. New ML-based methods were used for data management, and quantitative analysis of RV volume and ejection fraction (RVEF) was performed offline. RV structural and functional parameters were recorded using 3DE. CTEPH was diagnosed using right heart catheterization, and 62 patients underwent cardiac magnetic resonance to assess right heart function. Adverse clinical outcomes were defined as PH-related hospitalization with hemoptysis or increased RV failure, including conditions requiring balloon pulmonary angioplasty or pulmonary endarterectomy, as well as death.Results: The median follow-up time was 19.7 months . Among the 151 CTEPH patients, 72 experienced adverse clinical outcomes. Multivariate Cox proportional-hazard analysis showed that ML-based 3DE analysis of RVEF was a predictor of adverse clinical outcomes , 1.046~2.372; P = 0.030).Conclusions: The new ML-based 3DE algorithm is a promising technique for rapid 3D quantification of RV function in CTEPH patients. Chronic thromboembolic pulmonary hypertension (CTEPH) is a subgroup in the classification of PH, which differs from other types of PH with regards to patient characteristics, pathophysiology, and treatment . CTEPH iCTEPH disease progression is accompanied by different degrees of myocardial hypertrophy, and right heart failure is the primary cause of death in CTEPH patients. RV fibrosis is a sign of potential maladaptation as a result of increased afterload caused by myocardial PH . CardiacThe right cardiac chambers and ancillary structures have long been neglected in research, but an increasing number of studies have shown that the structure and function of the right heart predicts the prognosis of CTEPH patients. Three-dimensional echocardiography (3DE) allows accurate and repeatable measurements of RV size and function. Most recently, the application of artificial intelligence methods, including machine learning (ML) algorithm techniques, have been developed to automatically detect RV intima boundaries –9. The MThis prospective study was conducted according to the principles defined in the Declaration of Helsinki. The study protocol was approved by the Ethics Committee at Beijing Chao-yang Hospital. All participants in this study signed written informed consent forms prior to the initiation of this study.The diagnostic criteria of CTEPH were as follows: at rest, the mean pulmonary arterial pressure measured by the right heart catheter was ≥25 mmHg and pulmonary wedge pressure (PAWP) was ≤15 mmHg; ventilation/perfusion (V/Q) imaging had at least one large perfusion defect at one segment or two subsections; or the presence of pulmonary vascular lesions identified by computed tomography (CT), magnetic resonance imaging (MRI), and/or pulmonary angiography .Clinical evaluation, echocardiography, 6-minute walk test (6MWT), and laboratory biochemical tests at 48 h intervals  were collected and recorded from all participants. Sixty-two patients underwent cardiac magnetic resonance (CMR) examination within 72 h to determine RV volume and ejection fraction (RVEF).Demographic and baseline clinical characteristics of patients were obtained through hospital databases and telephone follow-up. Exclusion criteria included: incomplete clinical and catheter pressure data, atrial fibrillation, moderate or severe aortic and/or mitral valvular heart disease, and poor quality of echocardiographic images. The study began with the inclusion of 218 CTEPH patients. Among the original cohort, 34 patients did not have complete clinical and catheter pressure recording, 13 had atrial fibrillation, nine had valvular heart disease. There were 11 patients (5.04%) who failed to obtain satisfactory 3D parameters due to poor image quality that could not clearly track the endocardium. After application of the exclusion criteria, 151 patients were finally included in this study between April 2015 and July 2019 .Echocardiographic imaging was performed with a Philips EPIQ 7C . An X5-1 transducer (1–5 MHz) was equipped onto a Doppler ultrasound machine. In the breath-holding state, 3DE images were collected over a maximum of 6 beats in an apical four-chamber (4Ch) RV-focused dataset. Throughout the cardiac cycle scanning, the entire RV cavity was within the scan volume. The imaging depth and sector width were optimized for the maximum frame rate and the 3DE dataset was analyzed offline.Quantitative analysis of RV function was performed using a new ML method  for offline data management . According to the operating instructions of the software, a 3D dynamic surface model of the RV was generated, from which the RV end-diastolic volume (RVEDV) and end-systolic volume (RVESV) were fully-automated. RVEF was calculated according to the formula RVEF = (RVEDV–RVESV)/RVEDV .The following RV structural parameters measured using 3DE were recorded: RVEDV, RVEDV/body surface area (BSA), RVESV, RVESV/BSA, RV basal diameter, RV mid-diameter, RV longitudinal diameter, RV basal diameter/LV basal diameter, and LV end-diastolic eccentricity index. Pericardial effusion was also recorded.RV function was evaluated according to the 2015 American Society of Echocardiography guidelines for cardiac chamber quantification by echocardiography in adults , includiCMR was performed with a 3.0 Tesla magnetic resonance scanner  using a four-channel cardiac phased-array surface coil for data acquisition. All CMR data were transferred to a workstation  and analyzed with validated software . CMR was performed with the true fast imaging with the steady-state precession sequence  using retrospective electrocardiogram triggered during breath holding. The acquisition time per patient was 6–10 min. An experienced radiologist, who identified the endocardial and epicardial boundaries, semi-automatically segmented the right and left ventricles. The RV cavity included endocardial trabeculae. Disk summation was used to calculate RVEDV and RVESV, and RVEF was calculated using the standard formula mentioned above.A 7.5-French gauge Swan-Ganz thermodilution catheter  was inserted into the right inferior pulmonary artery through the internal jugular vein. The following parameters were measured under stable hemodynamics: RA pressure, mean PA pressure, pulmonary vascular resistance, and cardiac index. Cardiac output (CO) undergoing cardiac catheterization was measured using the thermodilution method. PVR in Wood units (WU) was calculated using the equation: PVR = –pulmonary artery wedge pressure)/CO. Echocardiography and RHC were performed with an interval of <72 h for all the patients.The primary end points in this study included the occurrence of adverse clinical outcomes defined as PH-related hospitalization with hemoptysis or increased RV failure, including conditions requiring balloon pulmonary angioplasty or pulmonary endarterectomy, as well as death. The cause of hospitalization or death was decided after reviewing the relevant medical history and documentation. Patients were all followed up until the occurrence of adverse clinical outcomes or the end of the study period.t-test was used to determine the significant difference of normally distributed data between groups. Pearson or Spearman correlation coefficients were used to assess the relationship between RVEF and other clinical and echocardiographic variables.All statistical analyses were performed using SPSS Version 23 , R version 3.6.3 , and MedCalc 16.1 . The one-sample Kolmogorov-Smirnov test was used to verify the normal distribution of all data. Abnormal data are expressed as frequency and percentage or mean ± standard deviation or median (interquartile range). The independent sample P-value < 0.10 in univariate analysis and prognostic parameters described previously. The survival receiver operating characteristic (ROC) curve was constructed to assess the sensitivity and specificity of predictors used to predict adverse clinical outcomes. The optimal survival threshold was predicted using the Youden's index method. Kaplan-Meier analysis was used to divide patients into quartiles based on RVEF. The incremental value of RVEF over baseline clinical models was estimated by the change in C statistic, whereas, the −2 log-likelihood test was used to estimate the relative fit of each model. We analyzed the consistency between CMR and 3DE measurements of RVEDV and RVESV. A bilateral P-value < 0.05 was considered statistically significant.Univariate Cox proportional hazards analysis was used to examine the association between the variables and the combined clinical endpoints, with results expressed as hazard ratios and bilateral 95% confidence intervals (CIs). Multivariate survival analysis included all variables with a A total of 151 CTEPH patients  and 30 age- and sex-matched healthy control subjects  constituted the study population . All patP < 0.0001). We found a correlation between RVEF and basic function parameters. For example, RVEF was positively associated with cardiac index  and 6MWD , but negatively associated with NT-proBNP . In addition, there was a strong negative correlation between RVEF and RV longitudinal strain   (The echocardiographic features of participants measured by ML-based 3DE are summarized in  0.0001) .r-values of 0.917 for RVEDV, 0.915 for RVESV, and 0.849 for RVEF . The 3DE measurements were appreciably accurate as reflected by biases of −10.21 ± 12.66 ml for RVEDV , −6.26 ± 11.66 ml for RVESV , and −0.24 ± 4.69% for RVEF , although, the ML-based software algorithm slightly underestimated all three parameters compared to CMR , and 72 patients (47.7%) experienced adverse clinical outcomes during this follow-up period: 66 patients were hospitalized because of disease aggravation, of which 45 were hospitalized due to decompensated right heart failure, 13 underwent balloon pulmonary angioplasty, and eight had pulmonary endarterectomy. In addition, six patients died of PH-related causes outside the hospital.The indicators of RV function and adverse clinical outcomes in the 151 patients are shown in two interquartile ranges in the middle of a group  and then analyzed the correlation with clinical deterioration. We found that a decrease in RVEF increased the risk of clinical deterioration, and that the prognosis of patients with an RVEF < 30.3% was poorer compared to patients with an RVEF > 44.6% , TAPSE, and RV fractional area change. Multivariate Cox proportional hazards analysis showed that ML-based 3DE RVEF and 6MWD had strong value for predicting adverse clinical outcomes . Kaplan- > 44.6% .P = 0.034, P < 0.0001)  .CTEPH patients are prone to have impaired RV function compared with normal subjects. In this prospective study, we introduced ML-based 3DE quantification of RVEF as a clinical means for predicting adverse clinical outcomes in CTEPH patients. We obtained the novel 3DE index, which easily combined information on RV volumes and RV function. We found that ML-based 3DE RVEF was a significant prognostic predictor for CTEPH patients.Because of the shape of the RV and its physical position in the chest, traditional echocardiography for the evaluation of cardiac remodeling for CTEPH patients remains challenging. To remedy the limitation of conventional echocardiography, 2DE was developed to use multiple views from different transducer locations to quantify RV size and function. Previously, we demonstrated that RT3DE was a viable, non-invasive, and accurate method for assessing RV systolic function in PH patients . In thisMeasurement of RV size and function is important for the diagnosis and prognosis of CTEPH patients. Currently, CMR is considered the gold standard for assessing RV size and function. However, its limited availability and high cost do not permit routine evaluation and follow-up of these patients. Echocardiography is still valuable for the diagnosis and follow-up of CTEPH patients and can provide functional information that is not available with CMR. ML-based 3DE RVEF, as a simple parameter, may be more useful in routine clinical management of CTEPH patients.In our CTEPH patient cohort, RVEF showed a correlation with basic clinical parameters, including cardiac index, 6MWD, and NT-proBNP. Our study demonstrated that CTEPH patients had a larger RV volume with a low RVEF and longitudinal strain compared with healthy controls. In addition, we found that RVEF, which was obtained by both echocardiography and CMR, correlated with RV functional parameters. More importantly, RVEF had a reinforced value in assessing disease severity because of the relation to cardiac index, 6MWD, and NT-proBNP. In line with our findings, a previous study reported that an increase in the RV/LV diameter ratio and high B-type natriuretic peptide levels were predictive of CTEPH development .CTEPH is a rare but complex pathophysiological disease characterized by chronic thrombo-mechanical obstruction, RV dysfunction, and secondary pulmonary artery lesions . A recenCardiac remodeling is defined as changes in RV shape, size, and function of the heart. RV morphology is more complex than LV morphology. Previously, Addetia et al.  partitioIn the subset of our study cohort who underwent CMR, the ML-derived 3DE measurements significantly correlated with CMR reference values for all parameters. Despite association with CMR-derived RVEF, widely used parameters such as TAPSE and S' only assess the lateral tricuspid valve ring. 2D speckle tracking echocardiography has been used to quantitatively determine RV myocardial deformation, but mainly focuses on longitudinal strain. In this study, we demonstrated the feasibility and high value of 3DE analysis to estimate RVEF and volumes in healthy volunteers and CTEPH patients using technical software. Our study showed that RV strain patterns gradually worsened in CTEPH patients and thus held an independent prognostic value. In particular, ML-based 3DE RVEF predicted the adverse clinical outcomes independent of those established prognostic markers, suggesting that it reflected additional information on cardiac physiology that was not available for other functional or imaging parameters. Consistent with our findings, Jone et al.  showed tIn the present study, we also found that RVLS  was an independent predictor of adverse clinical outcomes of CTEPH patients. RVLS indirectly but sensitively reflects RV function and hemodynamic changes in PH patients . MortaliOne major limitation of our study was the number of patients. As a result, this study included a relatively small number of adverse clinical outcomes, which prevented broader statistical analysis, especially for hard endpoints such as death. Also, due to the RV enlargement in CTEPH patients, the software automatic tracking system was not able to accurately identify the endocardial structure of the RV free wall if the RV expansion was severe or the display of the RV free wall was not clear. Nevertheless, we successfully captured quality images at the end of the exhalation period. In addition, because of the mentioned limitation, the RV volume measured by 3DE was smaller than that obtained by CMR. Finally, although, our study had a median follow-up time of 19.7 months, future studies should extend the follow-up time to ensure that the proportion of patients with poor prognosis due to right heart failure can be distinguished.ML-based 3DE RVEF is closely associated with RV systolic function and has a greater prognostic value than other recognized predictors for CTEPH patients. This new technique can help better stratify the risk of developing adverse clinical outcomes among CTEPH patients. Our study highlights the value of RVEF in risk assessment of CTEPH patients, but multi-center and larger cohort studies are needed to further corroborate our findings.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of Beijing Chao-yang Hospital. The patients/participants provided their written informed consent to participate in this study.YL and LL conceived and designed research. YL, YY, JG, XZ, and ZJ collected data and conducted research. LL and DZ analyzed and interpreted data. YL and DG wrote the initial paper. XL and YY revised the paper. YL had primary responsibility for final content. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We review the drug and device trials in adults with HF to highlight the knowledge gap that exists in the pediatric HF population.This review discusses the potential drug and device therapies for pediatric heart failure (HF) due to reduced systolic function. It is important to realize that most drugs that are used in pediatric HF are extrapolated from adult cardiology practices or consensus guidelines based on expert opinion rather than on evidence from controlled clinical trials. It is difficult to conclude whether the drugs that are well established in adult HF trials are also beneficial for children because of tremendous heterogeneity in the mechanism of HF in children and variations in the pharmacokinetics and pharmacodynamics of drugs from birth to adolescence. The lessons learned from adult trials can guide pediatric cardiologists to design clinical trials of the newer drugs that are in the pipeline to study their efficacy and safety in children with HF. This paper A working definition of heart failure (HF) in children is “a progressive clinical and pathophysiological syndrome caused by cardiovascular and noncardiovascular abnormalities that results in characteristic signs and symptoms including edema, respiratory distress, growth failure, and exercise intolerance and accompanied by circulatory, neurohormonal, and molecular derangements” . In adulThis review discusses the current and future pharmacological therapies in children with acute and chronic HF, the mechanism of action of drugs, and the need for future clinical trials in children for the safety and efficacy of newer drugs that are used in adults. Furthermore, we discuss the device therapies in adult HF and highlight the potential of these devices for pediatric HF, as we learn from adult trials.Acute HF syndrome (AHFS) is described as a structural or functional alteration in the heart that occurs rapidly, followed by congestion, malperfusion, hypotension, and end-organ dysfunction resulting in a need for hospitalization and urgent therapy . The goa2) antagonists (tolvaptan and conivaptan) can be used to enhance free-water excretion and correct hyponatremia. The EVEREST study in adults with HF demonstrated that tolvaptan improves edema, body weight, dyspnea, and sodium level, but there are no survival benefits [The management of AHFS relies on an accurate assessment of the patient’s congestion and adequacy of systemic perfusion . Adequatbenefits . Tolvaptbenefits ,8.Vasoactive drugs are used as a rescue therapy in AHFS to improve systemic perfusion and prevent end-organ dysfunction. These drugs improve myocardial contractility and when combined with appropriate blood pressure control, they may increase cardiac output. However, the use of vasoactive drugs in children with AHFS is mainly used as a bridge to transplant or mechanical circulatory support and is not recommended for maintenance therapy or recovery of heart muscle function . The conLevosimendan can be an alternative to milrinone for AHFS. It is not available in the US but is widely used in Europe. It is a calcium-sensitizing agent that binds to troponin-C, enhancing its sensitivity to intracellular calcium, and has positive inotropic action. It also opens up the adenosine triphosphate (ATP)-dependent potassium channels leading to smooth muscle relaxation, vasodilation, and decreased systemic vascular resistance. The hemodynamic effects of levosimendan include increased cardiac output and decreased filling pressure. It causes an increase in contractility without an increase in myocardial oxygen demand and has lusitropic action on the myocardium. Initial studies of levosimendan in adults , is identical to the endogenously produced BNP. It increases intracellular cyclic GMP (cGMP), resulting in vasodilation and a decrease in afterload. It inhibits neurohormonal activation, produces diuresis, natriuresis, and increases cardiac output . The effAfter presenting with AHFS, when the hemodynamics stabilize and end-organ functions recover, the child is often left with the lingering diagnosis of chronic HF syndrome (CHFS), with or without a genetically based or syndrome/systemic disease-based diagnosis. Several regulatory neurohumoral and counter-regulatory pathways are involved in the pathogenesis of CHFS .The goal of the clinical management of CHFS in children is to permit recovery, maintain stability, prevent progression, and provide a reasonable milieu to allow somatic growth and optimal development into adult life. Typically, a multi-drug approach is required, with either sequential combination therapy or upfront combination of angiotensin-converting enzyme inhibitors (ACEi), β-blockers, diuretics, and aldosterone antagonists. Herein we review the current and future landscape of drug therapies for chronic HF in adults with evidence for randomized clinical trials to highlight the knowledge gap in pediatric HF. Contrary to adults, the clinical trials to verify the safety and efficacy of drugs used in CHFS in children are limited .Renin-angiotensin-aldosterone system (RAAS) pathway activation is a central physiologic response to decreased renal perfusion and is characteristic of CHFS with reduced systolic function. Renin stimulates the conversion of hepatic angiotensinogen to angiotensin I, which is acted upon by the angiotensin-converting enzyme (ACE), predominantly in the lungs, to form angiotensin II, a potent vasoconstrictor that causes chronic deleterious effects in HF. These include the vasoconstriction of renal afferent arterioles and the release of aldosterone, which causes an increase in sodium reabsorption. When the RAAS activation is undeterred, vasoconstriction (increased afterload) leads to cardiomyocyte hypertrophy and apoptosis . FurtherClinical trials of adult patients with HF with reduced systolic function (CONSENSUS in 1987  and SOLVThe effect of angiotensin receptor blockers (ARBs) in HF is similar to that of ACEi. For patients intolerant of ACEi , an angiotensin receptor blocker (ARB) such as valsartan, losartan, or candesartan is often well-tolerated and effective . BecauseIn response to HF, the body compensates by activating the sympathetic nervous system, increasing circulating catecholamines . The phy’s HF clinical status [Numerous randomized controlled trials in adults have validated the beneficial effects of the β-adrenergic blockade in reducing symptoms, hospitalizations, and mortality related to chronic HF ,38,39. βl status ,41,42. Tl status .At the cellular level, the compensatory gain in cardiac excitation-contraction coupling mediated by sympathetic stimulation ultimately becomes unsuccessful, as the sustained leak of calcium from the sarcoplasmic reticulum leads to the depletion of intracellular calcium and ultimately impairs contractility . SeveralBased on the PARADIGM-HF trial’s success, the pediatric HF community has conducted a PANORAMA-HF study trial comparing sacubitril/valsartan to enalapril in children with Class C HF whose systemic ventricle is a LV with an ejection fraction <40% . This stFor adults, valsartan/sacubitril is available in three dosage strengths: 24/26 mg, 49/51 mg, and 97/103 mg. These doses are 50 mg, 100 mg, and 200 mg in the clinical trial . The tarf current inhibitor in the sinoatrial node, acts by reducing heart rate and helped reduce HF hospitalization and death from HF in adults in the SHIFT and BEAUTIFUL trials [Ivabradine, an IL trials . The safL trials . In thisOmecamtiv mecarbil is a new class of myotropes that binds selectively to the cardiac myosin protein base and permits ADP-P release from the myosin-actin-ATP complex, thus increasing the number of myosin heads that can bind to the actin filament and facilitate cardiac sarcomere contractility. As a result, there is increased systole duration but no increase in myocyte calcium, and no increase in myocardial oxygen consumption, unlike the vasoactive agents . The GALThe DAPA-HF trial  and the The cGMP pathway has been implicated as an essential regulator of endothelial function in both primary and secondary pulmonary hypertension and is relevant to myocardial and vascular smooth muscle dysfunction in HF states as well . Vericig+-K+ ATPase pump, thereby preventing Na+ removal from the myocytes in the exchange of K+. As a result, more intracellular Na+ available for calcium influx through the Na+-Ca++ exchanger. Calcium is transported into the sarcoplasmic reticulum and helps a more muscular mechanical contraction. Furthermore, evidence from experimental studies suggests that digoxin binds directly to ryanodine receptor-2 [Digoxin is a cardiac glycoside and was the cornerstone of HF therapy for decades until a paradigm shift in HF pathophysiology led to a shift from inotropic therapy to neurohormonal modulation. Digoxin binds to the sarcolemmal Naceptor-2 . Digoxinceptor-2 , RADIANCceptor-2 , and DIMceptor-2 . After dceptor-2 . Becauseceptor-2 .The use of digoxin in pediatric HF patients is largely empirically based but, in general, has been replaced by newer HF therapies for better neurohormonal modulation. However, a Pediatric Heart Network study recently showed that digoxin decreased interstage mortality significantly in infants with single ventricle physiology . DigoxinA few other drugs are under trial for AHFS in adults, including istaroxime  and HVAD®  are used with increased survival benefits and successfully bridged to heart transplantation [®  for children >19 kg based on the consortium data [Mechanical circulatory support with left ventricular assist devices (LVADs) are increasingly used to manage HF in infants and children as a bridge to transplantation or destination therapy in selected patient cohorts . In chilantation ,73. Receium data . Althougium data . There aThe potential for cardiac regeneration in children may be greater than in adults. It has been shown that there is myocyte regeneration after unloading of the dilated LV by mechanical circulatory support in pediatric dilated cardiomyopathy patients with end-stage HF . The regThere has been a rapid proliferation of clinical studies using stem cells in adults with HF , yet lit® (transcatheter MV Repair)  device was approved by the FDA in 2013 for adult patients who cannot tolerate surgery of the MV. The Cardiovascular Outcomes Assessment of the MitralClip® in Patients with HF and Secondary MR (COAPT) trial has provided a new option for managing selected adult patients with secondary MR and HF [The prognosis in HF patients who develop secondary mitral regurgitation (MR) due to dilatation of LV leading to annular dilatation of mitral valve (MV) is worse, with a direct quantitative relationship between the severity of MR and both death and hospitalizations for HF in adults . The MitR and HF . Many otR and HF  and SUMMR and HF , to inve® neo system  in 2019 to improve HF symptoms in adults. There is no experience of baroreflex activation therapy in pediatric HF.Autonomic dysregulation  leading to persistent tachycardia, increased oxygen demand, and higher afterload can cause the development and progression of HF . Afferen® System in Subjects with Moderate-to-Severe Heart Failure) trial has shown promising results in the symptomatic improvement of chronic HF in adults [® System) delivers a biphasic, long-duration (~20 milliseconds), high-voltage (~7.5 V) electrical signal to the septum of the RV during the absolute refractory period [Chronic HF due to decreased systolic function is characterized by abnormal intracellular calcium handling and mechanical and electrophysiological dysfunction . The FIXn adults . The cary period ,90. As ty period . There i®, Corvia Medical) [®  interatrial shunt device [The elevated left atrial pressure is the sine qua non of chronic HF, which is directly related to exercise intolerance. In adults, various minimally invasive devices such as the Inter Atrial Shunt Device   and the t device  have bee®  peritoneal direct sodium removal system in adults with chronic HF [® in pediatric HF.Chronic HF patients develop resistance to diuretics, and in adults, peritoneal direct sodium removal is a novel approach to treat volume overload. The RED DESERT study is an ongoing trial to investigate the feasibility and safety of the Alfapumpronic HF . There iThe ACC/AHA/HFSA guidelines for pharmacological therapy for HF in adults were updated in 2016 , and the


Patients’ short-term outcomes with the curved GOKU were excellent, with a significantly better percent increase in minimum lumen diameter of 0–220% (92% ± 66%) vs 0–46% (18% ± 15%) with the Sterling balloon (p < 00.1) and with less frequent balloon slippage. The curved GOKU was more effective in balloon angioplasty for acute-angled lesions compared with a conventional straight balloon, likely because of better conformability to the lesion angle and slip resistance.Obstruction develops commonly at the acute-angled portion of the vessels following palliative surgery, such as systemic–pulmonary shunt (SP shunt), right ventricle–to–pulmonary artery shunt (RV–PA shunt) in the Norwood–Sano procedure for hypoplastic left heart syndrome, and cavopulmonary (Glenn) anastomosis. Although balloon angioplasty is a treatment option, dilation with existing straight balloons is sometimes ineffective and technically complicated because of balloon slippage and target vessel distortion. In this study, we investigated the effectiveness of a curved GOKU balloon catheter for balloon angioplasty in postoperative acute-angled lesions associated with palliative surgery for congenital heart disease. We reviewed patients who underwent balloon angioplasty for angled lesions complicated by SP shunt, RV–PA shunt, or Glenn anastomosis, using the novel curved GOKU or a conventional balloon catheter, such as a Sterling balloon catheter. We evaluated patients’ backgrounds, balloon specifications, target lesion anatomical features and angles, and short-term outcomes. We evaluated 45 procedures in 18 patients. A curved GOKU was used in 20 procedures, and a Sterling balloon in 25 procedures. The angulation of the lesions at maximum balloon inflation was significantly smaller using a curved GOKU vs a Sterling balloon [70–120  degrees vs 110–180 (149 ± 46) degrees, respectively;  Obstruction develops commonly at the acute-angled portion of the vessels following palliative surgery, such as systemic–pulmonary shunt (SP shunt) We reviewed patients who underwent balloon angioplasty using the curved GOKU vs the Sterling balloon catheter, which is a conventional straight balloon with similar specifications to the curved GOKU, from January 2011 to May 2019 at Showa University Hospital and Showa University Northern Yokohama Hospital. Because the types of target lesions in balloon angioplasty varied in our patients, we extracted data of patients undergoing SP shunt, RV–PA shunt, or Glenn anastomosis for analysis, to clarify the effects of the differences between the two balloon types. The indications for balloon angioplasty were: (1) progressive desaturation or (2) scheduled unclipping of a previously-clipped conduit for SP shunt and RV–PA shunt; while for Glenn anastomosis, the indications were: (1) unexpected low oxygen saturation, (2) increased superior vena cava pressure, or (3) significant laterality of pulmonary blood flow. In SP shunt and RV–PA shunt, we selected a balloon diameter 1–2-mm larger than the diameter of the expanded polytetrafluoroethylene (ePTFE) graft used for the previous surgery, while in the Glenn anastomosis, we used a balloon measuring either 1–3 times to than the minimal lumen diameter, or not exceed 1.5 times of the reference vessel diameter. The curved GOKU was selected by operator’s preference based on the initial clinical experience We evaluated patients’ backgrounds, balloon specifications, target lesion anatomical features and angles, and acute outcomes. Regarding the anatomical features of the target lesions, we evaluated the minimum lumen diameter (MLD) of the target lesion and percent diameter stenosis (% DS), defined as [(reference vessel diameter-MLD)/reference vessel diameter] × 100, before and after the procedure, and the % increase in MLD, defined as [difference in MLD before and after procedure]/MLD, before the procedure. We defined the angle of the lesion as the angle formed by the proximal and distal vessels of the stenosis. The original angle of each lesion and the angle change at balloon inflation were measured on the angiograms using the most appropriate angled views; i.e., lateral view for RV–PA shut, and the frontal or left or right anterior oblique view for SP shunt or Glenn anastomosis. We also evaluated balloon slippage or displacement at inflation, which affects the effective dilation of the lesion. We compared these data between the two balloon catheter groups.p values < 0.05 were considered statistically significant. This study was approved by the Showa University Ethics Committee .Each parameter is expressed as mean ± standard deviation, and we used Wilcoxon’s rank-sum test to compare means between each variable. The chi-square test was used to evaluate the incidence of balloon slippage between the groups, and statistical analyses were performed using JMP® 10 . n = 5), hypoplastic left heart syndrome (n = 4), pulmonary atresia with the intact ventricular septum (n = 2), congenitally corrected transposition of the great arteries (n = 2), and tricuspid atresia, complete transposition of the great arteries, single left ventricle, double outlet right ventricle, and coarctation of the aorta with subaortic stenosis (n = 1 for each). Target lesions were associated with SP shunt in 10 patients, Glenn anastomosis in 5 patients, and RV–PA shunt in 3 patients. Details of the patients’ backgrounds, balloon specifications, target lesion anatomical features and angles, and short-term outcomes are shown in Table p < 0.001], while the original angle was similar in both groups. Furthermore, given the significantly small difference of only 12° between the original angulation and that at maximum balloon inflation, the curved GOKU showed better conformability than the Sterling balloon in acute-angled lesions. A representative angiogram and changes in the angles of the lesions at inflation for both balloon types are shown in Fig. p < 0.01). The incidence of balloon slippage in the curved GOKU group was 1/20 while 8/25 in the Sterling balloons group, which was not significant but tend to be lower in the curved GOKU (p = 0.07)  degrees in the groups. In bench testing, the curved angle of the curved GOKU is 90°, 88°, and 80° at 10, 13, and 18 atmospheres, respectively Regarding the disadvantage of this balloon, there is some limitation in rewrapping, which may cause difficulty to re-cross the stenosis. Acceptable but a little bit lower trackability compared to the Sterling balloon may be another limitation. Although no objective data is available associated with industrial secrets, we suppose these limitations are caused by its special characteristic of balloon wrapping to bend when inflated.There are limitations in this study. First, measurement errors in the angles based on two-dimensional angiograms of the three-dimensional lesions are possible. Second, we did not compare differences between the two balloons for the same lesion, and with identical balloon specifications . Finally, our patient numbers were low.Using a curved GOKU for angled lesions may allow for better conformability and prevent slippage at balloon inflation. The curved GOKU is more effective for balloon angioplasty in acute-angled lesions compared with a conventional straight balloon.


Right ventricular (RV) systolic function has an important role in the prediction of adverse outcomes, including mortality, in a wide range of cardiovascular (CV) conditions. Because of complex RV geometry and load dependency of the RV functional parameters, conventional echocardiographic parameters such as RV fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE), have limited prognostic power in a large number of patients. RV longitudinal strain overcame the majority of these limitations, as it is angle-independent, less load-dependent, highly reproducible, and measure regional myocardial deformation. It has a high predictive value in patients with pulmonary hypertension, heart failure, congenital heart disease, ischemic heart disease, pulmonary embolism, cardiomyopathies, and valvular disease. It enables detection of subclinical RV damage even when conventional parameters of RV systolic function are in the normal range. Even though cardiac magnetic resonance-derived RV longitudinal strain showed excellent predictive value, echocardiography-derived RV strain remains the method of choice for evaluation of RV mechanics primarily due to high availability. Despite a constantly growing body of evidence that support RV longitudinal strain evaluation in the majority of CV patients, its assessment has not become the part of the routine echocardiographic examination in the majority of echocardiographic laboratories. The aim of this clinical review was to summarize the current data about the predictive value of RV longitudinal strain in patients with pulmonary hypertension, heart failure and valvular heart diseases. The right ventricle (RV) has a complex anatomy and position in the thorax and therefore its assessment has long been limited and included a few conventional parameters that are easy to measure. Studies reported a significant prognostic effect of these RV parameters in a wide range of cardiovascular (CV) conditions such as pulmonary hypertension, congenital heart disease, pulmonary embolism, heart failure, cardiomyopathies, and valvular disease –6. InterRV longitudinal strain represents the cornerstone of RV mechanics evaluation with excellent reproducibility and high predictive value in patients with different aforementioned CV diseases –13. It hThe aim of this clinical review was to summarize the current data about the predictive value of RV longitudinal strain in patients with pulmonary hypertension, heart failure, and valvular diseases in order to emphasize the importance of its evaluation in routine echocardiographic examination in these conditions.The retrosternal position of the RV and its unique crescent-shaped geometry with inflow and outflow tracts in almost the same plane is challenging for echocardiographic assessment . SeveralThe evaluation of RV longitudinal strain is also performed in 4-chamber view, which certainly represents an advantage because it does not demand additional time for acquisition . RV wallThe technical aspects of image acquisition for speckle-tracking assessment are specific because they need to provide optimal images for post processing and high level of reproducibility for strain assessment. The suggested frame rate is between 40 and 90 frames per second for analysis of cardiac deformation. With increase of heart rate requires a higher frame rate to allow optimal speckle-tracking echocardiography. The acquisition of high-quality images is necessary for strain analysis, which considers the optimal gain settings and breath-hold techniques to clearly define the endocardial and epicardial borders and to avoid artifact associated to rib or lung motions and translational heart movement. RV focused apical 4-chamber view is necessary for RVLS evaluation. The optimal RV focused view should provide the visualization of the whole RV, the RV-free wall, and avoid foreshortening of the RV apex.There is still no consensus about the region of interest that should be included in evaluation of RVLS. Some authors suggest a full RV chamber six-segmental model including the interventricular septum into the calculation of RVLS, whereas more authors accepted a three-segmental model, which involves only the RV free wall . The sixThe normal values of RVLS are still a matter of debate. Study that included significant number of patients reported lower RVLS values in men than in women, independently of the three- or six-segment model . ReferenThere are several commercially available software platforms that enable post-process evaluation of raw data. EchoPac (GE) and TomTec are the most frequently used in clinical and research circumstances. EchoPac provided six-segment model and curve for each RV segment (including interventricular septum) and three-segmental model can be derived from these curves involving only segments of RV free wall. However, it is vendor dependent tool and can be used only for evaluation of echocardiographic images obtained by GE machines. TomTec is a vendor-independent software that can measure all echocardiographic images and provides automatically three-segment model for RV free-wall LS evaluation .RV strain has several advantages: angle-independency, less load-dependency, and accuracy in measurement of regional myocardial deformation. The major limitation of 2D RV strain is motion-dependent speckles loss outside the imaging plane, especially due to excessive motion of the RV lateral wall. Nevertheless, this has been largely overcome with the introduction of software that provides dedicated RV longitudinal strain analysis and separate evaluation of RV free-wall longitudinal strain and RV global longitudinal strain. The important limitations are also lack of agreement about method that should be used for RVLS evaluation (three- vs. six-model) and unknown normal values for RVLS. Advantages and limitations are presented in The majority of studies investigated the predictive role of RV longitudinal strain in patients with idiopathic pulmonary arterial hypertension (PAH), but the number of researches that examined patients with pulmonary hypertension in pulmonary diseases  and connective tissue diseases  is constantly increasing.In patients with PAH, conventional parameters of RV systolic function, including TAPSE, FAC, s′, and RVEF, may be normal despite abnormal RV strain, which is an additional reason for the usage of RV strain in these patients. RV longitudinal strain can identify subclinical RV dysfunction at the early phase of disease and may serve as an important marker of subtle RV systolic dysfunction when conventional parameters, primarily TAPSE, are in the normal range , 26.Small study that included 42 patients with PAH investigated the influence of different echocardiographic parameters on 4-year outcome and reported that RV free-wall longitudinal strain showed the best specificity and sensitivity in prediction of CV events in this population, significantly better than TAPSE, FAC, s′, and RV index of myocardial performance . PAH patBadagliacca et al.  recentlyNot only RV strain at baseline, but also its change during therapy and follow-up is important for prognosis of PAH patients. Hardegree et al.  reportedTable 4).Meta-analysis that involved 1,169 PH patients revealed that RV free-wall strain >-19% had a significantly higher risk for the combined endpoint , while patients with >-22% had a significantly higher risk for all-cause mortality . It showThe role of CMR-derived RV longitudinal strain in prediction of adverse outcome in PAH patients is insufficiently known because of scarce data. Recent study that included 80 PAH patients provided CMR analysis of all RV and right atrial (RA) structural, functional and strain parameters and showed that RV longitudinal strain, TAPSE, FAC, and RA longitudinal strain were predictors of adverse outcome in these patients . Sato etRV dysfunction is known indicator of poor survival in patients with heart failure (HF) . ConventInvestigations proved that RV longitudinal strain is deteriorated at early stage of HF . Data frStudy that involved patients with HFrEF referred for heart transplantation reported that free-wall and global RV longitudinal strains, NT-pro-BNP, FAC, and LV end-diastolic volume were independent predictors of combined outcome  . Free-waIacoviello et al.  demonstrThe investigation that combined echocardiographic analysis with myocardial histologic analysis reported that RV free-wall longitudinal strain was the main determinant of myocardial fibrosis, which may explain high prognostic value of this parameter in HF patients . RV freeIn patients with acute HF decompensation RV free-wall longitudinal strain was an independent predictor of cardiac events  . Other eBosch et al.  reportedThe effect of RV function in patients with valvular disease has been investigated in the last several years and it has become evident that effect of RV dysfunction on outcome in these patients is not irrelevant. The majority of studies reported deterioration of RV longitudinal strain in patients with valvular diseases , 62, butn = 101). Interestingly, TAPSE and FAC also significantly reduced after SAVR and remained the same in TAVR group  showed that RV longitudinal strain did not significantly improve after TAVR, but it significantly deteriorated in SAVR group, even though TAVR group had worse baseline clinical characteristics (more patients in NYHA class III and IV and significantly higher EuroSCORE) . HoweverVR group . This diVR group . The samVR group .Dahou et al.  investigResearch that included HF patients due to severe aortic stenosis undergoing TAVR reported that RV global longitudinal strain and RV-arterial coupling  provided better risk stratification than other RV echocardiographic parameters during long-term follow up of 10 years . TAPSE, Recent large study that involved 334 patients who underwent TAVR reported no significant change in RV free-wall longitudinal strain at 1-year follow-up, in both groups with baseline impaired and normal RV systolic function . HoweverRV systolic function is a very important in patients undergoing mitral valve surgery and some studies showed its strong predictive value for long-term mortality in a large population of patients who underwent cardiac surgery  . RV systStudy that involved patients who underwent mitral valve surgery reported significant deterioration of RV free-wall longitudinal strain in these patients . The autLarge research that involved 568 patients with severe ischemic mitral regurgitation who underwent surgical valve repair and 131 patients with concomitant tricuspid valve repair demonstrated that the RV continued to dilate while the LV reduced during follow-up after surgery . RVEF deFunctional mitral regurgitation has been currently treated with interventional “edge-to-edge” technique and study that investigated patients with moderate and severe mitral regurgitation, who underwent MitraClip procedure, demonstrated no acute improvement (within 7 days) in CMR-derived RVEF, RV end-diastolic volume and tricuspid regurgitation .Findings from aforementioned studies warrant further examinations to identify optimal timing and approach of intervention for functional mitral and tricuspid regurgitation.Isolated or concomitant functional tricuspid regurgitation has been extensively investigated in last decade. It has been shown that tricuspid regurgitation significantly deteriorated the outcome in patients with mitral regurgitation. However, surgical intervention seems not to improve RV function in these patients . InterveLarge study that included 1,089 patients with tricuspid regurgitation showed that reduced RV free-wall longitudinal strain (>-18%), TAPSE (<18.5 mm) and FAC (<35%) were independent predictors for 2-year all-cause mortality . The senInvestigation that enrolled 250 consecutive patients with severe tricuspid regurgitation investigated RV global and free-wall longitudinal strain and reclassified ~42–56% of patients with normal RV systolic function according to conventional parameters in patients with impaired RV systolic function . The autRecent study included 544 patients with severe functional tricuspid regurgitation with a median follow-up of 6 years . PatientCurrent studies support the evaluation of RV longitudinal strain due to its high predictive value in patients with tricuspid regurgitation. Data about the effect of interventional “edge-to-edge” tricuspid valve repair are expected and they will provide some new guidelines if RV longitudinal strain should be involved in routine echocardiographic examination and it seems that body of evidence that supports this evaluation is constantly enlarging.RV longitudinal strain is a significant parameter of RV dysfunction that showed better sensitivity than conventional echocardiographic parameters. Latest investigation demonstrated its role in prediction of adverse outcome in wide range of CV conditions, but the most encouraging data came from studies that were focused on pulmonary hypertension, HFrEF and tricuspid regurgitation. Data about the predictive importance of RV longitudinal strain in HFpEF patients and those with aortic stenosis and mitral regurgitation are still scarce and warrant further investigation. Adding RV longitudinal strain to existing scores might significantly help in the risk stratification, which could induce reclassification of some patients to higher risk group. Existing knowledge about the predictive value of RV longitudinal strain supports its routine echocardiographic evaluation in patients with CV diseases.MT wrote the article. NN, LS, JK, and CR reviewed the literature. JK made figures. DB, BG, and DS helped in preparing the text of the manuscript. EB, CC, and WR reviewed the article with important scientific input. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cancer patients may develop prognostic awareness (PA) heterogeneously, but predictors of PA‐transition patterns have never been studied. We aimed to identify transition patterns of PA and their associated factors during cancer patients’ last 6 months.For this secondary‐analysis study, PA was assessed among 334 cancer patients when they were first diagnosed as terminally ill and monthly till they died. PA was categorized into four states: (a) unknown and not wanting to know; (b) unknown but wanting to know; (c) inaccurate awareness; and (d) accurate awareness. The first and last PA states estimated by hidden Markov modeling were examined to identify their change patterns. Factors associated with distinct PA‐transition patterns were determined by multinomial logistic regressions focused on modifiable time‐varying variables assessed in the wave before the last PA assessment to ensure a clear time sequence for associating with PA‐transition patterns.Four PA‐transition patterns were identified: maintaining accurate PA (56.3%), gaining accurate PA (20.4%), heterogeneous PA (7.8%), and still avoiding PA (15.6%). Reported physician‐prognostic disclosure increased the likelihood of belonging to the maintaining‐accurate‐PA group than to other groups. Greater symptom distress predisposed patients to be in the still‐avoiding‐PA than the heterogeneous PA group. Patients with higher functional dependence and more anxiety/depressive symptoms were more and less likely to be in the heterogeneous PA group and in the still‐avoiding‐PA group, respectively, than in the maintaining‐ and gaining‐accurate PA groups.Cancer patients heterogeneously experienced PA‐transition patterns over their last 6 months. Physicians’ prognostic disclosure, and patients’ symptom distress, functional dependence, and anxiety/depressive symptoms, all modifiable by high‐quality end‐of‐life care, were associated with distinct PA‐transition patterns. Patients with cancer may not develop accurate prognostic awareness (PA) at the same rate or to the same degree and factors associated with PA‐transition patterns are unknown. Here, we identified PA‐transition patterns and their associated factors during the last six months of life for patients with advanced cancer and found that they developed PA in different ways. Four PA‐transition patterns were identified: maintaining accurate PA, gaining accurate PA, heterogeneous PA, and still avoiding PA. Prognostic disclosure by physicians, patient symptom distress, functional dependence, and anxiety/depression symptoms are major factors associated with PA‐transition patterns and can be acted on during high‐quality end‐of‐life care. Patients were asked if they knew their prognosis. If they did not know, subsequently they were asked to rate their desire for prognostic information  on a 5‐point Likert scale from 1  to 5 (“very desired”). Desire for prognostic information was dichotomized at the median score into wanting to know (≥3) and not wanting to know (<3). If patients knew their prognosis, subsequently they were asked whether their disease (a) was curable; (b) might recur in the future, but their life was not currently in danger; or (c) could not be cured, and they would probably die in the near future.Data analysis).Accordingly, patients’ PA was categorized into four states: (a) unknown and not wanting to know, (b) unknown but wanting to know, (c) inaccurate awareness, and (d) accurate awareness.3.2Based on Andersen's behavioral model,Demographics and clinical characteristics: Demographics included age, gender, marital status and educational level. Clinical characteristics were time since diagnosis and post‐enrollment survival.Reported physicians’ prognostic disclosure was measured by asking patients whether their physician had disclosed their prognoses to them. Responses were coded yes (“1”) and no (“0”).Disease burden: Physical symptoms and functional dependence were measured by the 13‐item Symptom Distress Scale (SDS)Emotional distress and social support: Emotional distress and social support were measured by the 14‐item Hospital Anxiety and Depression Scale (HADS)3.3Patients’ demographics and clinical characteristics were collected at enrollment. PA and time‐varying independent variables  were collected by trained, experienced oncology nurses at enrollment and approximately monthly until patients declined participation or died.3.4We used chi‐square tests and analysis of variance to compare baseline characteristics of patients in the final sample and those excluded from our analysis Appendix . PA statP values ≤0.05 were statistically significant.PA‐transition patterns were identified using the first and last PA states estimated by HMM. Factors associated with PA‐transition patterns were identified by multinomial logistic regressions. “Lagged measures” were used for time‐varying independent variables in the assessment wave before the last PA assessment to ensure a clear time sequence for associating with PA‐transition patterns. The regression estimate for each independent variable in the multinomial logistic regression models was exponentiated to transform into adjusted odds ratio (AOR) with 95% confidence interval (CI). 44.1Of 795 eligible patients, 460 were enrolled Figure . The 334n = 188, 56.3%), followed by unknown and not wanting to know  and unknown but wanting to know . Only 3.3% (n = 11) of participants had inaccurate PA , unknown and not wanting to know , unknown but wanting to know , and inaccurate PA   and approximately two‐thirds of those with unknown and not wanting to know PA  remained in the same PA state , followed by those with inaccurate PA  and those who did not know and did not want to know their prognosis . Specifically, four PA‐transition patterns  were identified: maintaining accurate PA (56.3%), gaining accurate PA (20.4%), heterogeneous PA (7.8%), and still avoiding PA (15.6%). The maintaining‐accurate‐PA group continuously had an accurate understanding of their prognosis. The gaining‐accurate‐PA group changed from not knowing their prognosis or from inaccurate PA to accurate PA. The heterogeneous‐PA group maintained inaccurate PA, maintained not knowing but wanting to know, or changed PA state from unknown and not wanting to know to inaccurate PA. Finally, the still‐avoiding‐PA group continuously did not know and did not want to know their prognosis.Between the first and last assessments, all patients with accurate PA  : maintaining accurate PA (56.3%), gaining accurate PA 20.4%), heterogeneous PA (7.8%), and still avoiding PA (15.6%). Drawing from the transtheoretical model (TTM),0.4%, hetOur findings show that factors modifiable by high‐quality EOL care, that is, physicians’ prognostic disclosure, and patients’ symptom distress, functional dependence, anxiety symptoms, and depressive symptoms are associated with patients’ membership in the four distinct PA‐transition patterns. Reported physician‐prognostic disclosure predisposes patients to belong to the maintaining‐accurate‐PA group than to the other three groups. Indeed, patients whose physician had disclosed prognosis toFurthermore, patients who reported physicians disclosing prognosis to them were more likely to be in the gaining‐accurate‐PA group than in the still‐avoiding‐PA group. Our finding re‐confirms that physicians’ prognostic disclosure is the key to patients’ gaining accurate PA rather than remaining in the still‐avoiding‐PA group.We found that patients with greater symptom distress were more likely to be in the still‐avoiding‐PA group than in the heterogeneous‐PA group. Furthermore, patients with greater functional impairment were more likely to be in the heterogeneous‐PA group than in the maintaining‐ and gaining‐accurate‐PA groups. Worse physical function/well‐being facilitates accurate PAIn contrast, patients with more anxiety and depressive symptoms were less likely to belong to the still‐avoiding‐PA group than to the maintaining‐ or gaining‐accurate‐PA groups, respectively, as reported,Demographically, older patients were more likely to be in the still‐avoiding‐PA group than in the maintaining‐accurate‐PA group, as reported.Clinically, patients who survived longer after their terminal status was first recognized by their oncologist were less likely to be in the heterogeneous‐PA and the still‐avoiding‐PA groups than in the maintaining‐ or gaining‐accurate‐PA groups. When cancer patients’ terminal/advanced status is recognized late, they may not have sufficient time for prognostic discussions and disclosure.5.1Our study has several limitations. Generalization of our findings to national and international target populations may be limited because participants were sampled from a single medical center in Taiwan. Our findings should be replicated for advanced cancer patients in countries with different cultural, societal, and healthcare characteristics, especially around physicians’ prognostic disclosure. Furthermore, we excluded a noticeable proportion of patients from our analysis that did not provide sufficient monthly data for detecting PA‐transition patterns. We conducted a sensitivity test to include the 48 participants who were assessed only twice in a single month Table  and foun5.2Cancer patients experienced heterogeneous PA‐transition patterns over their last 6 months. Physicians’ prognostic disclosure, and patients’ symptom distress, functional dependence, anxiety symptoms, and depressive symptoms are major factors associated with patients’ membership in the distinct PA‐transition patterns and are modifiable through high‐quality EOL care. Physicians’ prognostic disclosure is the key to gaining and maintaining accurate PA. Therefore, physicians should be sensitive to patients’ prognostic‐information needs/desires and repeatedly initiate prognostic discussions earlier in the illness trajectory to facilitate/consolidate cancer patients accurate PA.Healthcare professionals should not neglect the prognostic‐information needs of patients in the heterogeneous‐PA and still‐avoiding‐PA groups with greater symptom distress and functional dependence: to develop accurate PA these patients need adequate symptom management to relieve physical symptom distress and facilitate functioning, frequent assessment of their readiness for prognostic information, and prognostic discussions appropriately tailored to their prognostic‐information needs.Furthermore, patients’ psychological distress (anxiety and depressive symptoms) may drive and facilitate accurate PA through worry about disease progression, earnestness to acquire prognostic information, and eager participation in prognostic discussions. Therefore, healthcare professionals should tailor prognostic discussions to the prognostic‐information needs of cancer patients with high anxiety and depressive symptoms and provide sufficient emotional support  with adequate referrals for psychological services after prognostic disclosure.The institutional review board approval: 101‐0898A3.The authors declare no financial or other conflict of interest.No funding sources had any role in designing and conducting the study; collecting, managing, analyzing, and interpreting the data; or preparing, reviewing, or approving the article.Supplementary MaterialClick here for additional data file.


T2-weighted signal hyperintensities in white matter (WM) are a diagnostic finding in brain magnetic resonance imaging (MRI) of patients with metachromatic leukodystrophy (MLD). In our systematic investigation of the evolution of T2-hyperintensities in patients with the late-infantile form, we describe and characterize T2-pseudonormalization in the advanced stage of the natural disease course.The volume of T2-hyperintensities was quantified in 34 MRIs of 27 children with late-infantile MLD . In three children with the most advanced clinical course (age >4 years) and for whom the T2-pseudonormalization was the most pronounced, WM microstructure was investigated using a multimodal MRI protocol, including diffusion-weighted imaging, MR spectroscopy (MRS), myelin water fraction (MWF), magnetization transfer ratio (MTR), T1-mapping and quantitative susceptibility mapping.T2-hyperintensities in cerebral WM returned to normal in large areas of 3 patients in the advanced disease stage. Multimodal assessment of WM microstructure in areas with T2-pseudonormalization revealed highly decreased values for NAA, neurite density, isotropic water, mean and radial kurtosis, MWF and MTR, as well as increased radial diffusivity.In late-infantile MLD patients, we found T2-pseudonormalization in WM tissue with highly abnormal microstructure characterizing the most advanced disease stage. Pathological hallmarks might be a loss of myelin, but also neuronal loss as well as increased tissue density due to gliosis and accumulated storage material. These results suggest that a multimodal MRI protocol using more specific microstructural parameters than T2-weighted sequences should be used when evaluating the effect of treatment trials in MLD. Metachromatic leukodystrophy (MLD) is an autosomal recessive inherited lysosomal storage disease caused by the deficiency of the lysosomal sulfatide degrading enzyme arylsulfatase A. The resulting accumulation of sulfatides in the central nervous system leads to the dysfunction and progressive destruction of microglia and oligodendrocytes , 2. ThisWhile MRI has been used mainly as a diagnostic tool early in the disease course, there are usually no MRIs available in the advanced disease stage, especially in the late-infantile form where there is severe and rapid disease progression; however, with new therapeutic options currently being evaluated in clinical trials in children with the late-infantile form of the disease , there iTherefore, it is necessary to assess cerebral tissue changes throughout the whole clinical course using MRI sequences, which can characterize and quantify white matter microstructure , 14 to pWe applied these sequences in a multimodal MRI protocol to children with late-infantile type MLD in the advanced stage of the natural disease course so to investigate their principal benefit regarding MRI changes in metachromatic leukodystrophy. These patients were of special interest because they showed intriguing findings with areas of normal T2 intensities in the white matter despite the late stage of the disease and thus contradicted the aforementioned current understanding of the MRI course of the disease.Patient data were collected as part of a natural history study of the German leukodystrophy network Leukonet . We inclHealthy subject data for the advanced sequence parameters were acquired and analyzed in advance to establish a control cohort that consisted of 21 healthy subjects developing typically .The MRI sequences of 23 patients were acquired on 1.5T and 3 T scanners and consisted of conventional clinical routine images with a high-resolution T1-weighted sequence  and a T2-weighted axial sequence  [3) .Axial T2-weighted turbo-spin echo  .MPRAGE  .MP2RAGE . Diffusion weighting gradients were applied in 64 directions with b = 2000 s/mm2 and 30 directions with b = 700 s/mm2. For distortion correction, an additional image without diffusion weighting was acquired with the same resolution, FOV and readout band width, but with reversed polarity of the phase-encoding gradients. N = 20 controls, 3 patients.Diffusion-weighted (DW) images using a high angular resolution, twice-refocused spin echo planar imaging sequence . N = 11 controls, 3 patients.MR spectroscopy using a chemical-shift imaging (CSI) sequence with the same axial orientation as the axial T2-weighted image positioned above the lateral ventricles . In addition, a B1 map was acquired from the same slice and used for MWF quantification. N = 19 controls, 3 patients).Myelin water fraction (MWF) imaging, using a Carr-Purcell-Meiboom-Gill (CPMG) sequence modified to have shorter radiofrequency (RF) pulse durations and increased band width of the 180° RF pulse.  images  and quantitive susceptibility maps (QSM) at eight different echo times  with an extended MR protocol, as done for the control cohort, explained in detail elsewhere . Please Image processing and data analysis were performed as previously described , 13.As mentioned before, to quantify the volume of T2 hyperintense white matter, the demyelination load was measured in all 26 patients using multispectral segmentation of high-resolution T1-weighted and axial T2-weighted images , 21. The2 [Correction for motion, EPI distortions and/or variation in signal intensity was applied to the DWI data set . Maps of2 , 23. Axi2 . Moreove2 .MRI spectra were analyzed quantitatively using the LCModel . Absolut2 regularization of 1.02, range of T2-values for the myelin water: 15–40 ms and for the remainder: 40–200 ms.For MWF all parameters including the flip angle, were fitted . In the The MT ratio (MTR) map was calculated in percentage units from the co-registered non-MT and MT images using the following equation: (non-MT − MT) / non-MT.For QSM the frequency maps were fitted by using the phase unwrapping and multi-echo fitting tool from the MEDI-Toolbox  and the www.github.com/MRtrix3/mrtrix3 [www.mathworks.com) and FSL tools  and interpolated to the subject’s FA map; therefore, it was made sure that all image modalities per subject were transformed into the same space and image dimensions for further analysis. Images were processed and analyzed using MRtrix , Matlabiki/FSL, ).Fig. www.r-project.org).Demyelination load  was correlated with the patient’s age and a regression analysis was performed using a quadratic regression model to estimate the mean change over time and its 95% confidence intervals using R  in the centrum semiovale within the corticospinal tract (CST-CS). The CST was delineated using tractography based on constrained spherical deconvolution. The ROI was set manually within the level of the CSI and MWF slice, above the level of the lateral ventricles, as done before .p-values <0.05 were considered as significant.The values of the ROIs were determined in both hemispheres of the brain  and the mean value and standard deviation of the corresponding ROI per group  were calculated. A statistical analysis was conducted using the Mann-Whitney U‑test comparing the group level results between the ROI locations of the patient and control group, while p-values for these analyses were not corrected for multiple comparisons and can, therefore, be regarded as descriptive.As this study was considered exploratory with a relatively small sample size, the The determined demyelination load depending on the patient’s age is shown in Fig. Fig. In the 3 patients with a demyelination load reduction or stable WM conditions multimodal imaging was supplemented to better characterize the microstructure of the WM. Fig. The raw values can be found in Table Most of the parameters recorded showed significant changes compared to the control group.In the parameters measured by diffusion-weighted imaging, FA, MD and RD were significantly altered, with FA showing decreased values whilst MD and RD increased values. Mean, axial and radial kurtosis also showed significantly decreased values compared to the control group.p < 0.001 except ODI, which was only slightly less significant with p < 0.008). The ICVF and ISO were reduced in the patient group, ODI increased.All NODDI-derived parameters  were significantly different from the control group .In contrast, QSM, R2* and quantitative T1 values lacked statistical significance. The qT1-values tended to be elevated in patients; however, this difference was not statistically significant , magnetization transfer ratio (MTR), effective transverse relaxation rate R2*, T1-mapping and quantitative susceptibility mapping.Many of the parameters tested here showed significantly different results when compared to the control group. First and foremost, the diffusion imaging parameters including most of the diffusion tensor values, diffusion kurtosis values and NODDI-derived parameters, MWF and MTR should be mentioned in this context, which achieved high effect sizes. In the following, the positive parameters are listed, interpreted and correlated with the literature, if available:Fractional anisotropy (FA) is decreased in patients, reflecting an increased diffusivity of water molecules than in healthy tissue as an expression of reduced fiber density or myelination. Radial diffusivity (RD), which is considered a correlate of myelin loss , is incrDiffusion kurtosis as an expression of the deviation from a Gaussian normal distribution is determined by the complexity of the tissue that limits the diffusivity of water molecules. It can, therefore, be regarded as a measure of the degree of the tissue structure . SimilarNODDI-derived parameters allow a further interpretation of the microstructure by assuming a compartmentalization of the tissue . The ICVWhile the total T2 signal was normal in patients, the T2 distribution arising from myelin water (between 10 and 40 ms for humans in vivo) is highlighted in the myelin water fraction . Lower vThe magnetization transfer ratio is significantly lower in patients. Since myelin in the white matter builds a significant proportion of the macromolecules that are involved in the magnetization transfer effect, this indicates a loss of myelin, as has been repeatedly demonstrated in multiple sclerosis , 52.In MR spectroscopy, only the quotient of N‑acetylaspartate to creatine (NAA/Cr), which is considered a correlate for neuronal integrity , 54, wasAs a comparison to other diseases, the phenomenon of normal appearing T2 signal in the white matter (NAWM) in combination with significant changes in advanced imaging techniques, as used in our study, is described in the context of patients with multiple sclerosis –60 and tIn connection with the current research question, some parameters remained without evidence of differentiation between patients and healthy controls. While QSM and R2* maps in multiple sclerosis have been shown to be a sensitive disease marker also for different stages of demyelination  , 63, thiTaken together, these MR parameters characterize the microstructure in areas with T2-pseudonormalization as a predominantly demyelinating process , but also suggest a loss of axons and fiber structure beyond this  as well as very dense tissue without free water molecules .The mechanism of the decrease of the T2 signal can be speculated according to these results but also to histopathological findings reported in MLD patients. Initially, the demyelinating component is predominant due to the accumulation of sulfatides in oligodendrocytes , the conHowever, it should be noted that the mechanisms of T2 normalization cannot be conclusively clarified in the absence of direct histopathological examination of tissues of the examined patients.Limitations of the current study are the small number of cases, the different sizes of the control groups and especially the small group size in QSM, R2* and qT1map, the asymmetric age of the control groups compared to patients and the lack of follow-up for the more advanced sequence parameters over the course of the disease. Furthermore, data collection was carried out in favor of the feasible scanning time in only 1 ROI. To increase the spatial extent of measurements, future studies might refrain from collecting the parameters that we found to be non-significant.However, it can be stated based on the available data that imaging extended by these parameters is useful in MLD patients in order to better quantify the extent of affected tissue, to better understand pathomechanisms and the resulting symptoms in the course of the disease, and to provide more reliable markers for therapy studies than T2 values, which, as described here, can also deceptively indicate normal values despite severe alterations, which could also be misinterpreted as a positive response to treatment. To a certain extent, this can probably also be transferred to the other forms of MLD  or other leukodystrophies with available therapeutic approaches, such as Krabbeʼs disease.We found a pseudonormalization of the disease-characteristic T2-signal changes in the late stage of late-infantile MLD. In the context of treatment trials in which MRI serves as an objective parameter for the course of the disease, this phenomenon could erroneously be interpreted as a therapeutic response. In addition, the T2 signal does not provide sufficient information about microstructural damage corresponding to a pathomechanism in MLD that goes beyond demyelination processes. We therefore recommend additional sequences in measurement protocols that can detect microstructural damage despite pseudonormalization. In particular, the diffusion weighted parameters MD, RD, the NODDI-derived parameters ICVF, ODI and ISO, the diffusion kurtosis parameters AK, RK and MK, MWF and MTR as well as MR-spectroscopy for NAA/Cr have been shown to be highly significant markers.