Background: Managing repaired tetralogy of Fallot (TOF) patients is still challenging despite the fact that published studies identified prognostic clinical or imaging data with rather good negative predictive accuracy but weak positive predictive accuracy. Heterogeneity of the initial anatomy, the surgical approach, and the complexity of the mechanism leading to dilation and ventricular dysfunction explain the challenge of predicting the adverse event in this population. Therefore, risk stratification and management of this population remain poorly standardized. Design: The CMR/CT WG of the Italian Pediatric Cardiology Society set up a multicenter observational clinical database of repaired TOF evaluations. This registry will enroll patients retrospectively and prospectively assessed by CMR for clinical indication in many congenital heart diseases (CHD) Italian centers. Data collection in a dedicated platform will include surgical history, clinical data, imaging data, and adverse cardiac events at 6 years of follow-up. Summary: The multicenter repaired TOF clinical database will collect data on patients evaluated by CMR in many CHD centers in Italy. The registry has been set up to allow future research studies in this population to improve clinical/surgical management and risk stratification of this population. Tetralogy of Fallot (TOF) is the most frequent cyanotic congenital heart disease (CHD), with an incidence estimated at 1/3500 live births. The latter is represented by four distinctive features: a perimembranous ventricular septal defect (VSD), the aortic root that overrides the septum, and therefore also the VSD, accompanied by right ventricular (RV) hypertrophy, and right ventricular outflow tract (RVOT) obstruction; the latter derived from the malalignment and the anteriorly deviation of the conal septum. .From the late 70s to nowadays, cardiac surgery has rapidly evolved and improved. This has permitted childhood intra-cardiac TOF corrections and has allowed the majority of the TOF patients (more than 90%) to survive to adulthood. This population of patients that underwent TOF cardiac surgery during childhood, live to date with a repaired TOF and may present with a wide range of residual anatomical/hemodynamic/thoracic residual issues, needing to be addressed in the future in their life. However, their optimal treatment is hampered by their heterogeneity due to significant differences in initial cardiac/pulmonary anatomy, surgical techniques of repair, as well as the era of them and subsequent surgical/interventional procedures along the follow-up ,2.The RVOT obstruction can occur at multiple levels ; therefore, it is very common that TOF may be accompanied by infundibular pulmonic stenosis and annular hypoplasia of the pulmonary valve, the main pulmonary artery, and branches, along with any peripheral pulmonary artery stenosis .The surgical repair consists of the closure of the interventricular defect and relief of the obstruction of the right outflow tract, resecting the RV infundibular muscularity, and very often extending the incision to the pulmonary annulus, opening it utilizing a trans-annular patch. In more severe cases, pulmonary pathway-associated anomalies need to be addressed. All this, inevitably, causes severe pulmonary valve dysfunction that, together with an RV infundibulum negatively remodeled, leads to an RV overload ,2,3,4.In addition, ROVT aneurysmal dilatation, succeeding pulmonary regurgitation, anastomotic site stenosis, main/branches pulmonary arteries stenosis, and distortions, along with progressive aortic root dilatation and subsequent aortic regurgitation, biventricular failure, and residual VSD, are also possible as follow-up sequelae ,2,3. It It is well known that the repair leads to right ventricular scarring and the extension of such myocardial fibrosis is documented on the cardiac magnetic resonance (CMR) by the presence of late gadolinium enhancement (LGE). Scar burden visualized by magnetic resonance imaging has been shown to be predictive for inducible VT in this population. In fact, myocardial fibrosis results in decreased myocardial contractility and relaxation, and serves as a potential substrate for scar-induced VT. Similarly, other measures such as myocardial strain and rotation patterns, location and extent of myocardial fibrosis, LV systolic circumferential strain rate, and other parameters derived from magnetic resonance all contribute to our understanding of higher-risk substrates for VT. Given that the method of performing the surgical correction has changed over time, from a transannular patch with a transventricular approach to that with a transatrial approach, the obvious consequence is that even the surgical era is also associated with risk of VT. Arrhythmias are the most important problem to be taken into consideration in TOF. It has been estimated that in the long-term follow-up of TOF patients, 30% of patients will have atrial arrhythmia and 10% will have complex ventricular arrhythmia, and the mortality risk triples after the third postoperative decade, with sudden cardiac death (SCD) being the most common cause of late mortality ,3,4,5.Pulmonary valve replacement (PVR) is recommended, at some moment of the patient’s life, as the best choice to resolve the RV overload due to pulmonary valve incompetence preventing the progressive exercise intolerance, arrhythmia due to the right heart failure, and sudden death. However, to this day, indications and optimal timing of PVR are unclear in the asymptomatic population, and the extent to which PVR really improves survival is still unknown since it does not completely eliminate right ventricular scarring. In addition, the bioprostheses valves used for PVR are destined to deteriorate in a short time, both for the structural valve failure and the increased risk for endocarditis ,4,6.Given all these premises, it is clear that many questions regarding the follow-up and late management, along with a risk stratification, of repaired TOF are still unanswered, with an imperative need to be addressed. Hence, the multicenter repaired TOF clinical database registry, that we here present, has been set up to allow future research studies in this population to improve clinical/surgical management and risk stratification of this population.In clinical practice, the diagnosis and monitoring of any residual defects and adverse events in this population are based on clinical evaluation and ECG on non-invasive imaging diagnostic tools. Echocardiography remains the first-choice method; however, CMR is considered the method of choice for measuring volumes and functions  and evaluating pulmonary regurgitation and the distribution of flows in the pulmonary branches. Moreover, thanks to the ability to characterize the myocardium, CMR allows for evaluating both focal and diffuse myocardial fibrosis. Therefore, CMR has a pivotal role in the lifelong follow-up and decision-making process for the repaired TOF population .A pulmonary valve of adequate size for the body surface, surgical or interventional implanted, is today the only therapeutic option to contrast progressive right ventricular dilatation. However, there is currently no valve or pulmonary conduit of lifelong duration. Therefore, multiple procedures are often necessary over a lifetime. In addition, there is no clear evidence that the pulmonary valve reduces arrhythmia or improves survival in this population .Published studies identified prognostic clinical or imaging data with good negative predictive accuracy but weak positive predictive accuracy . The incTherefore, risk stratification and management of this population remain poorly standardized and debated. Also, there is a lack of knowledge of very long-term survival due to only 40–50 years of follow-up available for repaired TOF ,14,15.Multicenter clinical databases are helpful for the evaluation and the study of chronic diseases, reducing the heterogeneity of the population enrolled and improving the statistical empowerment .The CMR/CT WG of the Italian Pediatric Cardiology Society clinical database of repaired TOF involves many pediatric cardiology centers managing and treating treatment CHD in Italy. Its aim is to collect a large cohort of repaired TOF anamnestic, clinical, imaging data, and adverse events. The study data will be included in further studies to contribute to identifying anamnestic and clinical-instrumental parameters predictive of adverse events in repaired TOF patients and, therefore, contribute to improving clinical and surgical management of this complex population.This observational study will include all eligible patients retrospectively and/or prospectively repaired TOF patients who were evaluated for a CMR study in participating in a CMR Lab from 1 January 2004 to 31 December 2024. Eighteen Italian CMR sites have accepted to participate in this study. Eight have already received the local ethical committee’s approval and started the data collection. The study has also been registered on ClinicalTrials.gov with the ID: NCT05288894. This study protocol also follows and adheres to the SPIRIT recommendations.Patients with repaired TOF/pulmonary atresia + VSD, double outlet right ventricle (DORV);Age > 10 years, as CMR is indicated in younger patients only in exceptional cases.Different associated complex pathology such as MAPCAs, atrioventricular canal or Ebstein;Incomplete CMR study;Patients who do not consent to the study;Contraindication to CMR.Data will be recorded into a web-based case report form that will be accessible through a restricted web-based site for the Fallot-CMR Multicenter Italian Database, developed as centralized support to the network of centers.The multicenter repaired TOF clinical database is based on the Rare Diseases Platform (RDP), a software for clinical data management already used to develop and support other patient registries such as the Dravet syndrome Italian registry and European RESIDRAS Platform (REF); the Tuscany registry for development of mental and epileptic encephalopathies and medical comorbidities (REMEDIES) for the DECODE-EE project; and the celiac disease Tuscany registry.RDP implements a web-based application, which allows different hospitals or research centers to manage a patient’s medical records. Medical records keep a patient’s clinical history, where some data can be entered once, and some are serials. As a rule, the investigator can access only the information associated with the medical records created and maintained within the hospitals.However, to support the cooperation among centers, the information can be shared among hospitals with different approaches, i.e., one possible technique consists of requesting a medical record that is subsequently handed over to another hospital. Data extraction in tabular form is available for any managed entity where required data is pseudonymized to mask fields that could lead to the disclosure of personal data belonging to a single patient.For the multicenter repaired TOF clinical database, the most relevant anamnestic, clinical, and imaging data of repaired TOF were identified.The platform is designed to manage health data; hence, particular attention is paid to personal data protection. These requirements are addressed by the General Data Protection Regulation (GDPR), and the data are managed and stored according to the highest standards in data management.Patients will be assigned a unique identification code by which they will be identified. The enrollment site will give the identification number after a patient consents to participate in the registry. The link between the patient and the associated identification number will remain at the enrolling center under restricted access.Each participating center will be responsible for collecting demographic, anamnestic, clinical, and image data sets defined by this study. In addition, any adverse events in the follow-up will be organized.The list of variables that will be collected is itemized in Demographic information form;Baseline information about the patient’s health at the time of enrollment;Anthropometric data;Pre-operative anatomy data: native anatomy impacts the surgical and interventional history of repaired TOF, therefore, when available, the data about the annulus and pulmonary branches anatomy, as well as associated extracardiac defects, will be collected  data: QRS length and QRS fragmentation were both identified as risk factors for adverse events in repaired TOF. Moreover, data from Holter monitoring, when available as significant atrial or ventricular arrhythmias, will also be reported  data: TTE is the first diagnostic tool in this population, allowing the evaluation of many of the anatomic and hemodynamic abnormalities in this population [pulation . In partpulation ,18. TherCardiac Magnetic Resonance (CMR) data: CMR is the gold standard. CMR is considered the reference standard for quantifying RV size, function, and PR in patients with repaired TOF [ired TOF ,15. BiveCardiopulmonary test (CPET) data: CPET is routinely used in the function evaluation in repaired TOF and provides prognostic predictors in this population. Therefore, any available date, Vo2 mL/kg/min, predicted, Vo2/HR, as well as the type of the protocol used, are included [included ,22  data: CC is mainly restricted in repaired TOF for interventional procedures and when non-invasive evaluation is inconclusive. In case of any cardiac catheterization, the date about atrial and ventricular pressure can be recorded [recorded ,22.Cardiac tomography (CT) data: even if a CT scan is rarely indicated in the routine follow-up, in selected cases with contraindication to CMR or for the evaluation of ferromagnetic device, a CT scan could be useful for the evaluation of coronary arteries, conduit calcification. A CT scan may also be considered as an alternative for ventricular quantification in patients unable to undergo CMR [ergo CMR . CT dataBrain natriuretic peptides (Nt-ProBNP and BNP) are prognostic biomarkers in this population and will be also recorded [recorded ,23.At the follow-up, any interventional or surgical procedures performed and symptoms or any events will be collected .The data collected would be suitable for longitudinal studies and outcome studies.Any investigator can suggest a study by submitting the idea, starting with a hypothesis. The idea will be discussed among members and with the proponent/s. If the scientific committee accepts the idea, the dataset of the deidentified data needed for the study will be available to the proponent.Sudden cardiac death;ICD implantation;Sustained ventricular arrhythmias;Non sustained ventricular arrhythmias;Atrial flutter, atrial fibrillation;Supraventricular tachycardia (SVT) consisted of an abrupt salve of three or more consecutive atrial premature beats at a rate of >100 beats per minute;Palpitations associated with syncope or near syncope in patients subsequently found to have inducible sustained SVT;Worsening of CMR data in particular dilation of the right ventricle, worsening of bi-ventricular function and heart failure.The mains endpoints collected in this clinical database will be:Demographic, clinical, CPET, TTE, and CMR data are summarized in n = 797 (90%), while DORV Fallot type was n = 22 (3%). Age at surgical repair 1.71 (0.75–4.8) and trans-annular patch (TAP) was the most utilized technique for primary RVOT repair, n = 553 (63%).During the last years, the data of 880 repaired TOF  have been collected. The most frequent diagnosis was tetralogy of Fallot The main characteristics of preliminary study population are listed in TOF is the most frequent cyanotic CHD during childhood. In addition, TOF comprises the largest numbers of patients, repaired during their childhood, that currently have survived to adulthood. It has been established that TOF may present in both children and adults with a wide heterogeneity of anatomical, hemodynamical, and thoracic features that can be difficult to correct and address at the moment of their first cardiac surgery. These post-operative issues can also be challenging to manage, both medically or procedurally, during the early post-operative period and later on. In addition, this heterogeneity mentioned above may affect and determine later outcomes. In fact, it has been largely recognized that preoperative decisions determine not only the peri-operative outcomes but impacts also on the long-term complications of this population ,16,24. TDuring the follow-up, the principal aims of future surgical and procedural treatments of TOF patients is mainly conditioned by cardiac anatomy, secondly by its function beyond the patient’s clinical state and/or symptoms, and thirdly if TOF is accompanied by syndromes like Trisomy 21, RASopathies, or similar ,25,26.In this context, cardiac imaging plays a key role, especially CMR. However, cardiac dimensions, volumes, and velocities derive by the assumption that TOF hearts can be assimilated to “normal” ones; therefore, RV imaging parameters, achieved from the general population, are adapted. Along with the RV morphology and function, the pulmonary arterial pathway is also particularly important in TOF patients. The pulmonary trunk, main pulmonary arteries (right and left), and peripheral vessels may recognize differences if compared to normal subjects. Lastly, the tricuspid valve dysfunction can co-exist beside an inevitably right atrial wall surgical incision. This is particularly important when evaluating the entire right cardiac structures, which will never act as “normal” for all the reasons mentioned above. Furthermore, it must be considered that although the three-dimensional evaluation with CMR is the most accurate tool to evaluate the right ventricle in TOF patients, there is an interindividual and between individual’s variability in the evaluation of the right ventricle when using this method ,22,27.As a matter of fact, and despite an ongoing interest in the repaired TOF population, the clinical management of these patients and their risk stratification is still imperfect, needing to be refined and tailored to any single TOF patient. In this context, the implementation of standardized protocols  seems to be necessary, even if not mandatory. Moreover, it has been recognized that the experience of any single institution is limited in this context. Different centers adopt different strategies to follow up, treat, and manage childhood repaired TOF during their adulthood .We thus hypothesized that this large multicenter study would help to improve the risk stratification in this population. Furthermore, we hope and expect that the studies, implemented by the registry, will allow for well-powered outcomes and longitudinal studies.Therefore, our aim with this large multicenter study should help to improve the risk stratification in this population. In fact, the right time to perform PVR in repaired TOF patients is still unclear, mainly in those who are asymptomatic. Thus far, basing PVR decision on MRI-assessed right ventricular size in these patients has failed. We found ourselves a population needing to replace the pulmonary prosthetic valve after a few years with a right ventricular re-dilatation associated with RV dysfunction. We must also consider that a percentage of these patients are younger than 18 years old. All this in the belief that the success in terms of survival of PVR was due to the normal return of the dimensions of the RV as well as the fact that the risk of sudden death at a certain threshold value of right ventricular dimension was higher than that of undergoing PVR with all the medium and long-term consequences of this approach. Only recently have some authors questioned these beliefs, and attempts are being made to postpone the timing of PVR in some completely asymptomatic patients without significant right ventricular dysfunction. Therefore, we hope that this registry will provide us with the possibility of identifying which patients with tetralogy of Fallot are, indeed, at risk of fatal ventricular arrhythmia and/or RV dysfunction and consequently to optimize the timing of PVR ,25,26,27In this context, we prospect more and more collaboration between centers, and this should be mandatory in order to gain farther comprehension regarding possible and/or late complications of repaired TOF and to have enough understanding of these problems. In addition, the implementation of a national registry may permit to conduct further meaningful outcomes analyses, without the occurrence of single-center-driven bias management.The multicenter repaired TOF clinical database will collect data of patients evaluated by CMR in most CHD centers of Italy. The registry has been set up to allow future research studies in this population to improve clinical/surgical management and risk stratification of this population.Generating a structured report would allow standardization of the CMR report among the participating centers and could help centers with less expertise;Integration of the multicenter study Fallot study platform with PACS (picture archiving and communication system) through a specific customized intermediate software would allow for the delivery of anonymized DICOM images into a temporary storage;Extending the study to other Italian or Europeans centers.Potentials for future development are:


Diagnosis of myocardial fibrosis is commonly performed with late gadolinium contrast-enhanced (CE) cardiac magnetic resonance (CMR), which might be contraindicated or unavailable. Coronary computed tomography (CCT) is emerging as an alternative to CMR. We sought to evaluate whether a deep learning (DL) model could allow identification of myocardial fibrosis from routine early CE-CCT images.n = 15, 30%) or non-ischemic  LVD. Delayed enhancement regions were manually traced on late CE-CCT using CE-CMR as reference. On early CE-CCT images, the myocardial sectors were extracted according to AHA 16-segment model and labeled as with scar or not, based on the late CE-CCT manual tracing. A DL model was developed to classify each segment. A total of 44,187 LV segments were analyzed, resulting in accuracy of 71% and area under the ROC curve of 76% (95% CI: 72%−81%), while, with the bull’s eye segmental comparison of CE-CMR and respective early CE-CCT findings, an 89% agreement was achieved.Fifty consecutive patients with known left ventricular (LV) dysfunction (LVD) underwent both CE-CMR and (early and late) CE-CCT. According to the CE-CMR patterns, patients were classified as ischemic (DL on early CE-CCT acquisition may allow detection of LV sectors affected with myocardial fibrosis, thus without additional contrast-agent administration or radiational dose. Such tool might reduce the user interaction and visual inspection with benefit in both efforts and time. Nowadays, gadolinium (Gd) contrast-enhanced (CE) cardiac magnetic resonance (CMR) imaging represents the gold-standard technique for the diagnosis and assessment of myocardial fibrosis . HoweverThe CE-cardiac computed tomography (CCT) was recently demonstrated to be a potential accurate alternative to CMR for the identification of myocardial fibrosis . The AHAThe introduction in the clinical setting of artificial intelligence (AI) to process cardiac images has showed remarkable performance in both diagnosis and prognosis . We hypo2.2.1.A consecutive cohort of fifty patients with an established diagnosis of LV dysfunction (LV ejection fraction <50%) undergoing CE-CMR between 2019 and 2020 were retrospectively selected from an Institutional resource program . CCT was2.2.As previously indicated , CMR was2.3.K = 0.014 mSv/mGy/cm)  with slice configuration 256 × 0.625 mm, spatial resolution 0.230 mm along the X–Y planes, rotational speed time 280 ms and prospective ECG triggering. Scans were performed during the end-inspiratory phase using the breath-hold technique with patients in the supine position. Coronary images were acquired covering the entire cardiac cycle (R-R phases from 0% to 100%), after intravenous injection of 1.5 ml/kg of contrast medium (Iomeron 400 mg/ml), sub-divided into two boluses: 80 ml contrast medium through an antecubital vein at an infusion rate of 5 ml/s, followed by 50 ml saline solution and a second bolus of contrast medium to reach the predetermined total dose of contrast medium. Imaging was performed using the bolus tracking technique. A second series of ECG-gated breath-hold CE-CCT images was acquired for myocardial delayed enhancement after 8 min from the first contrast-agent injection . Late CE-CCT images were reconstructed at 75% of the R-R interval using soft kernel and 0.625 mm slice thickness. The effective dose was calculated as the dose-length product times a conversion coefficient for the chest  of equal length perpendicular to its long axis, thus generating three groups  of SAX slices for the LV. For the basal section, only slices where the myocardium surrounds completely the LV were further considered for analysis. The apical cap was excluded from the apical section as recommended  Supplem. Then, t2.5.For model training, each image corresponding to a myocardial sector in the early CE-CCT was cropped to reduce the processing area, and resized into 85 × 85 pixels. In addition, videointensity values in Hounsfield units were normalized to zero mean and unit variance.https://keras.io/) and consisted of 4 convolutional layers. The number of filters was set to 32, 64, 96 and 96, respectively. After each convolutional layer of kernel size 3 × 3, the feature volumes were down-sampled by a max-pooling layer with 2 × 2 pixels window. On top of the network, three fully-connected layers  preceded the classification layer. After each max-pooling layer, batch normalization was implemented to make the training process faster and less sensitive to the learning rates. A random dropout of 30% was applied during training in each fully connected layer to prevent overfitting. The Rectified Linear Unit (ReLU) was used as activation function in all layers except the final one, where the sigmoid function was used. Training was performed from scratch using Adam optimizer with the initial learning rate set to 1 × 10−3 to minimize the binary cross-entropy loss function. The rate will be multiplied by a factor of 0.2 once the validation loss does not continuously reduce over 6 epochs, and the training phase will end when it reaches 1 × 10−7.To obtain the binary classification of myocardial tissue in scar/no scar, early CE-CCT sectors constituted the input of an end-to-end DL classification model based on a custom 2D-Convolutional Neural Network (CNN), together with the provided classification. The CNN was built within the DL framework Tensorflow-Keras  was applied until a balanced ratio with the minority class (scar label) was reached.2.6.To evaluate the classification performance, based on the ground truth evaluation built on the late CE-CCT images, a 5-fold cross-validation strategy  was perfTo compare this performance in a per-patient analysis with the CE-CMR gold standard, the 16-segment AHA model relevant to the presence/absence of a delayed enhancement in the early CE-CCT image was compared with the corresponding 16-segment CE-CMR model. More details about the AHA-sectors subdivision and analysis can be found in Continuous variables were expressed as mean ± standard deviation (SD) or median (25th−75th percentiles), whereas categorical data were given as absolute value and percentage, as appropriate. Confidence intervals (CI) were set at 95%. Agreement between CCT and CMR in the number of myocardial segments involved was assessed with the Cohen K statistic.3.3.1.Baseline characteristics of the study group  are reported in According to early CE-CCT evaluation, 17 patients presented significant coronary artery disease: nine patients presented single-vessel disease, three had a two-vessel disease and 5 reported a triple vessel disease. For details on the segmental involvement and the respective CE-CMR pattern  see 3.2.Of the initial 44,187 sectors computed out of the 8,285 slices available from the early CE-CCT images, 4,594 sectors (10%) presented scar, of which, according to the threshold condition based on the scar manual tracing, 1,090 were excluded, 3,504 (8%) were labeled as scar, and 39,593 (92%) were labelled as no scar.On the early CE-CCT images, a classification accuracy of 71% was obtained through the 5-fold cross validation . The meaRepresentative examples of the classification process for one slice at basal, mid and apical levels is given in In a per-segment analysis of the 16-segment AHA model, 708 out of 784 sectors were correctly classified, thus resulting in a total accuracy from the early CE-CCT of 89%  compared to the CE-CMR. The concordance between the model prediction and CMR assessment of CE extent is shown in According to the visual analysis on late CE-CCT scan, the agreement with the CE-CMR was 82% . Results of the comparison between the 16-segment AHA model from the CE-CMR and that from the early CE-CCT, as determined by the CNN, is illustrated in 4.An automatic AI system based on CNN for myocardial tissue classification from early CE-CCT imaging was developed and evaluated. Our results showed that its use in routinely noninvasive coronary imaging, without the need of a dedicated CCT acquisition, thus potentially eliminating the need for additional contrast-agent administration or radiation dose, enables myocardial fibrosis detection (AUC 0.76). Further, on a per-segment basis of the 16-segment model, the proposed method seemed to perform slightly better than the expert clinical myocardial fibrosis evaluation based on late CE-CCT scan (CNN accuracy 89% vs. 82% for expert). These results might pave the way towards a future approach for scar detection parallel to CMR, especially for those patients precluded from contrast-agent.Besides the promising results, automatic sector classification did not reach always satisfactory results. A possible hypothesis could be that images of some patients were more critical to be classified than others. Accordingly, the effect of the classification accuracy for different patient classes  was examined. A lower performance in patients with an ischemic pattern over non-ischemic pattern was observed, in particular relevant to the decrease in NPV. Nevertheless, these findings may be of clinical relevance as automatic analysis of the 16-segment AHA model showed appreciable accuracy for both ischemic (86%) and non-ischemic (92%) cardiomyopathy patients, above the clinical observation accuracy on late CE-CCT .Although CE-CMR imaging represents the reference technique for locating and qualifying myocardial fibrosis , it invoCurrently, the acquisition protocol for the delayed enhancement CCT imaging is based on injection of large volumes of iodinated contrast-agents (at least 1.5 ml/kg) which might cause different complications , 26, besSo far, only few studies investigated how to detect myocardial fibrosis from routine coronary CCT using AI-based approaches. A first attempt exploiting DL for the identification of ischemic myocardial fibrosis from early CE-CCT was proposed in . HoweverIn line with previous studies, results suggest the potential role of AI-based technologies as a support for individual-level diagnosis into routine workflow, classifying myocardial sectors affected by fibrosis using early-enhanced CCT images, even when this is not clearly visible by human eyes. Besides the promising results, our study is not free from limitations. First, the image quality of the late CE-CCT, from which scar manual tracing was performed, is worse than that of the CE-CMR, thus potentially introducing under- or over-estimation in the scar size, which might explain the cause for false positives in CNN diagnoses. As our aim was to analyze all slices covering the LV included in the CCT volume, using scar manual tracing on CE-CMR would not have provided the proper reference, due to its limited number of slices. Accordingly, our choice of performing scar manual tracing on late CE-CCT, while having available as reference the CE-CMR images, was taken as an attempt to minimize the described above limitations. Second, considering that there is no consensus on the optimal time delay when to acquire late CE-CCT with sufficiently good image quality, and that only a single attempt should be performed to limit the exposure of patient to x-rays, the same time delay was applied in all the acquired patients. This setting could have limited the image quality in same patients, thus potentially affecting the manual segmentation accuracy, and raising the hypothesis that variability in performance between ischemic and non-ischemic patients might be likely related to image quality. Third, possible misalignment among early and late CE-CCT slices due to heart rate variation or different breath-holding needed to be adjusted when visually detected by manually re-setting the long-axis. In addition, this evaluation was performed as a single-center study using the same scanner for all the acquisitions, so further external evaluation  is required to prove generalizability of our CNN model. Also, a larger training population could further improve the performance. Unfortunately, it is not common for patients to undergo both CMR and CCT in such a short window time, so specific research protocols need to be performed for this aim. Fourth, large volume of iodinated contrast-agent was used to account for the detection of myocardial delayed enhancement, thus potentially hampering the model’s performance at lower concentration of contrast agent. Finally, while scar location and scar tissue area lead to different prognoses , where tWe addressed the challenging topic of myocardial fibrosis from routine noninvasive coronary scans. To this end, a novel AI system for myocardial characterization was proposed. The results suggest that the developed method has the potential to classify both ischemic and non-ischemic myocardial fibrosis sectors from early CE-CCT acquisition, thus removing the need of additional contrast-agent administration or radiations. This might potentially facilitate the investigation and management of patients with LV dysfunction and coronary artery disease. Further, being CE-CCT more widely available than CE-CMR, it could place CCT in a favorable position for a faster myocardial tissue characterization than CE-CMR.


The prognosis of patients with dilated cardiomyopathy (DCM) is poor and new indicators are urgently needed to predict lethal cardiac events. This study aimed to investigate the value of summed motion score (SMS) in predicting cardiac death of DCM patients using gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI).99mTc-MIBI gated SPECT MPI were retrospectively enrolled and were divided into cardiac death and survivor groups. The functional parameters of left ventricle including SMS were measured using quantitative gated SPECT software. During the follow-up period of 44  months, 14 (17.28%) cardiac deaths were observed. Compared with the survivor group, SMS was significantly higher in the cardiac death group. Multivariate cox regression analysis showed that SMS was an independent predictor for cardiac death . SMS also provided incremental prognostic value over other variables in the multivariate model as determined by likelihood ratio global chi-squared test. In the Kaplan-Meier survival analysis, the event-free survival rate was significantly lower in the high-SMS (HSMS) group than the low-SMS (LSMS) (log-rank P < 0.001). Furthermore, the area under curve (AUC) of SMS was larger than that of LVEF at the 12th month of follow-up .Eighty-one patients with DCM who underwent SMS is an independent predictor of cardiac death in DCM patients and provides incremental prognostic value. SMS might have higher predictive value than LVEF for early cardiac death. DCM Studies have shown that regional wall motion obtained from gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) provides important prognostic information on cardiovascular outcome events –7. For e2.2.1.Eighty-one patients with DCM were retrospectively enrolled in this study at the First Hospital of Shanxi Medical University from January 2015 to July 2020. These patients were eligible to be enrolled after their diagnosis were confirmed, based on medical history, clinical, electrocardiographic, and echocardiographic findings according to the recommendation criteria –16. Pati2.2.99mTc was provided by Beijing Atomic High-tech Co. LTD, with radiochemical purity >95%; MIBI was purchased from Jiangsu Institute of Atomic Medicine. To perform gated SPECT MPI, each patient underwent intravenous injection of 20–30 mCi of 99mTc-MIBI in an overnight fast state, followed by a fatty meal 20 min after tracer injection, and resting gated SPECT MPI scan was performed 60 min after injection. The MPI images were acquired on a dual-collimator instrument  using a standard protocol. Image acquisition parameters: SMART-ZOOM collimator, energy peak 140 keV, matrix 128 × 128, magnification 1.0, acquisition of myocardial images in ECG gated tomography mode, and ECG window width 20%. The two probes were rotated at an angle of 76° and images were acquired total for 208° from a right anterior oblique 38° to a left posterior oblique 66°. The acquisition speed was 25 sec per frame, and 34 frames were acquired in approximately 8 min. The ordered-subsets expectation maximization (OSEM) method was used to reconstruct the image  and to obtain the myocardial tomographic images at the left ventricular (LV) short axis, horizontal long axis and vertical long axis.The 2.3.Gated SPECT tomograms were reconstructed and reoriented using automated software . A 17-segment model  was used to analyze the gated SPECT data , 20. Qua2.4.Follow-up data were obtained through phone contact with patients or their relatives, and other information of patients were obtained from the records of the hospitalized case system. The endpoint was cardiac death, including cardiac arrest or death from circulatory failure occurring within the first hour or refractory chronic heart failure . The mea2.5.U test and were expressed as M . The categorical variable adopted the chi-square test or nonparametric Fisher’s exact test and was presented as number and percentage.R4.1.2 software and IBM SPSS Statistics 28.0 were used for statistical analysis. Package “survminer” was used to find the cut-off value for SMS, and the population was divided into high-SMS (HSMS) and low-SMS (LSMS) groups based on the cut-off value of SMS. The quantitative data adopted the Mann–Whitney P < 0.05 in univariable cox regression analysis were included in multivariable Cox regression analysis. For any variable included in the cox model, the proportional hazard assumption was not rejected. In addition, Spearman’s correlation was used to illustrate the strength of an association between imaging indicators.The Kaplan-Meier method was used to obtain the event-free survival curve, and the log-rank test was used for comparison; univariable cox survival analysis and least absolute shrinkage and selection operator (LASSO) regression were performed to assess the association of each variable with survival outcome. The method of LASSO was used to select LV function parameters. Univariable cox regression analysis was used to calculate the hazard ratio (HR) and the 95% confidence interval (95% CI) of each variable. Multivariable cox regression analysis was used to determine independent predictors of adverse events. The deviation residuals were drawn for continuous variables to check the hypothesis of proportional hazards. Variables with P < 0.05 was considered to be statistically significant.We also used global likelihood-ratio Chi-square statistics to evaluate the incremental value of different models including clinical variables (clin) only, clin + SMS, clin + conventional LV function parameters (con LV), and clin + SMS + con LV. In addition, time-dependent receiver operating characteristic (ROC) curves were used to evaluate the performance of the indicators; Package “time ROC” was used to draw ROC curves between different imaging indicators in different times and to compare the area under the curve (AUC) of them. 3.3.1.P < 0.05). Of all the patients, 4 (5.0%) were classified as having NYHA functional class I, 10 (12.3%) as NYHA class II, 39 (48.1%) as NYHA class III, and 28 (34.6%) as NYHA class IV. All patients received guideline-directed medication for heart failure. The use of β-blocker in the survivor group was significantly higher than that in the cardiac death group . There was no significant difference in the use of ACE inhibitors/ARBs, diuretics and digoxin between the two groups. There was also no significant difference in hypertension, diabetes, hyperlipidemia, LBBB, mitral regurgitation and LVEF measured by echocardiography (LVEFecho) between the two groups. The QRS duration was longer in the cardiac death group than in the survivor group .P = 0.001) and greater EDV and ESV . Compared with the survivor group, the cardiac death group had higher SMS , higher STS , and larger PE . There was no significant difference in other mechanical contraction synchrony parameters PBW, PSD and mean between the two groups. P = 0.035), longer QRS duration (P = 0.019), more NYHA class III/IV cases (P = 0.045) and lower LVEFecho (P = 0.001). There was no statistical difference in age, sex, hypertension, diabetes, hyperlipidemia, LBBB, mitral regurgitation and medication use  between LSMS and HSMS groups. Compared with the LSMS group, the HSMS group had significantly lower LVEF (P < 0.05), significantly higher SMS (P < 0.001), and significantly larger values of EDV, ESV, STS, mean and PE (P < 0.05). The differences in PBW and PSD between the LSMS and HSMS groups were not statistically significant.3.2.β-blockers, EDV, ESV, LVEF, SMS, STS and PE were associated with cardiac death  (P = 0.034). Age and β-blockers were also influential factors for cardiac death  ,  < 0.05) . These p < 0.05) , and fin= 0.024) .β-blockers, diuretics, digoxin, LVEFecho, EDV, ESV, LVEF, STS, PBW, mean, PSD and PE. In addition, our results showed that SMS was significantly associated with LVEF  (P = 0.972) (P < 0.05).< 0.001) . To clar= 0.972) , indicat3.3.P < 0.001) and adding the conventional LV function parameters (con LV) increased the global Chi-square from 12.845 to 42.624 (P < 0.001) compared to clinical variables only. Adding SMS to the model that included clinical variables and con LV still improved the global Chi-square   .3.4.P < 0.001). The higher the SMS, the worse the prognosis (P = 0.045), and there was no significant difference in the AUC between SMS and LVEF at other follow-up times  months, cardiac death occurred in 14 (17.28%) of the total 81 patients. The Kaplan-Meier event-free survival curve showed that the HSMS group had a lower event-free survival rate than the LSMS group , we still confirmed that SMS was an independent predictor of cardiac death in patients with DCM. Previous studies  in cardiovascular disease –25. Ther studies , 30, 31  studies  are likefindings , 33.The pathophysiological mechanisms of segmental ventricular wall motion abnormalities in DCM are unclear. Based on previous studies, we considered that several factors may be involved in the mechanisms. First, LV structural and functional parameters, including partial volume effects caused by myocardial wall thinning and increased local wall stress, reduction of blood perfusion due to cardiomyocyte loss, increase of intra-diastolic myocardial pressure, and myocardial fibrotic changes , 34, 35,P < 0.001) (shown in P < 0.001) (P = 0.047) , adding SMS increased the global Chi-square from 12.845 to 28.120  . The add= 0.047) . We alsor = 0.72) (r = 0.917), possibly because both of the two parameters were obtained through gated SPECT MPI and were consistent. Our study also showed a reduction in LVEF in the HSMS group compared to the LSMS group . However, LVEF reflects the global function, and the hypercontractile cardiomyopathy segments may offset the hypokinetic cardiomyopathy segments, thereby preserving total LV systolic function  months, we found that the AUC of the ROC curve of SMS was relatively stable around 0.80 at all timepoints, suggesting that SMS is relatively stable in predicting cardiac death. It is well known that the LV global functional parameter LVEF is an important predictor of cardiac death in patients with DCM 5, 54 mon. The glo = 0.72) , 41. Ourfunction . Studiesfunction –45. In aInterestingly, we found that the AUC of the ROC curve for SMS was larger than that of LVEF at the 12th month after follow-up, suggesting that SMS is more predictive of early cardiac death in DCM. One possible explanation of this phenomenon is that compensatory hyperkinesia of non-involved myocardium may not affect the ventricular wall motion score while limit the overall LVEF reduction, therefore the sensitivity of the ventricular wall motion score is higher than LVEF in detecting myocardial injury, especially in the early stage of cardiac diseases , 47.5.Our study had some limitations. First, the study was retrospective with recall bias. Second, the study was a single-center study, thus the findings might not be generalizable to a broad population. Third, the relatively smaller sample size may have limited the statistical power. Forth, this study used a relatively high tracer dose and an all-purpose gamma camera. In the future, we may improve these limitations by conducting similar studies in multicentered and larger population using new equipment.6.We report for the first time that SMS can independently predict cardiac death in patients with DCM and provide incremental prognostic value. These findings may be clinically important to anticipate patients’ conditions in advance, to increase clinical attention, and to prolong patient survival. In addition, we found that SMS might have higher predictive value than LVEF for early cardiac death.


Various complications of pituitary neuroendocrine tumors (PitNET) are reported, and an intratumor hemorrhage or infarct underlying pituitary apoplexy (PA) represents an uncommon, yet potentially life-threatening, feature, and thus early recognition and prompt intervention are important. Our purpose is to overview PA from clinical presentation to management and outcome. This is a narrative review of the English-language, PubMed-based original articles from 2012 to 2022 concerning PA, with the exception of pregnancy- and COVID-19-associated PA, and non-spontaneous PA (prior specific therapy for PitNET). We identified 194 original papers including 1452 patients with PA . Clinical presentation included severe headache in the majority of cases ; neuro-ophthalmic panel with nausea and vomiting, meningism, and cerebral ischemia; respectively, decreased visual acuity to complete blindness in two cases; visual field defects: hemianopia, cranial nerve palsies manifesting as diplopia in the majority, followed by ptosis and ophthalmoplegia ; proptosis (N = 2 cases). Risk factors are high blood pressure followed by diabetes mellitus as the main elements. Qualitative analysis also pointed out infections, trauma, hematologic conditions , Takotsubo cardiomyopathy, and T3 thyrotoxicosis. Iatrogenic elements may be classified into three main categories: medication, diagnostic tests and techniques, and surgical procedures. The first group is dominated by anticoagulant and antiplatelet drugs; additionally, at a low level of statistical evidence, we mention androgen deprivation therapy for prostate cancer, chemotherapy, thyroxine therapy, oral contraceptives, and phosphodiesterase 5 inhibitors. The second category includes a dexamethasone suppression test, clomiphene use, combined endocrine stimulation tests, and a regadenoson myocardial perfusion scan. The third category involves major surgery, laparoscopic surgery, coronary artery bypass surgery, mitral valvuloplasty, endonasal surgery, and lumbar fusion surgery in a prone position. PA in PitNETs still represents a challenging condition requiring a multidisciplinary team from first presentation to short- and long-term management. Controversies involve the specific panel of risk factors and adequate protocols with concern to neurosurgical decisions and their timing versus conservative approach. The present decade-based analysis, to our knowledge the largest so far on published cases, confirms a lack of unanimous approach and criteria of intervention, a large panel of circumstantial events, and potential triggers with different levels of statistical significance, in addition to a heterogeneous clinical picture  and a spectrum of evolution that varies from spontaneous remission and control of PitNET-associated hormonal excess to exitus. Awareness is mandatory. A total of 25 cohorts have been published so far with more than 10 PA cases/studies, whereas the largest cohorts enrolled around 100 patients. Further studies are necessary. Various complications have been reported in the relationships of pituitary neuroendocrine tumors (PitNET); an intratumor hemorrhage or infarct/infarction, also named pituitary apoplexy (PA), is a less common feature, yet with a life-threatening potential, thus its importance in early recognition and prompt intervention. Of historical note, hemorrhages associated with pituitary tumors were first described in 1898 by Pearce Bailey, and in 1950 the term “pituitary apoplexy” was introduced by Brougham et al. ,3. The incidence of PA in the general population varies from 0.2% to 0.6%, and from 2% to 12% in selected subgroups diagnosed with different types of PitNETs ,5. MalesThe underlying mechanisms of PA are not completely understood yet. The classical hypothesis states that a rapidly growing tumor exceeds vascular supply . Other pIn terms of clinical presentations, sudden headache, often with retro-orbital location, is one of the most common presenting symptoms of PA, with an incidence of 92% up to 100% of the patients . The PA-The imaging tests used as a diagnostic aid are mostly represented by computed tomography (CT) and magnetic resonance imaging (MRI) . Even thPA management involves a multidisciplinary team, as it is considered a neuroendocrine emergency. The main source of mortality is caused by acute adrenal insufficiency. Therefore, prompt glucocorticoid replacement is crucial . HoweverOur purpose is to overview PA as a complication of a pituitary tumor, particularly PitNETs, from clinical presentation to management and outcome.This is a narrative review of the English-language medical literature. Inclusion criteria are the following: clinically relevant papers concerning a PubMed-based search using the keywords “apoplexy”, “hemorrhage”, or “infarction” in association with “pituitary” ; the timeline of publication is between 2012 and 2022; we included original research, either studies or case reports/series. Exclusion criteria were PA associated with the following circumstances: pregnancy and postpartum period, infection with coronavirus amid the recent COVID-19 pandemic, and non-spontaneous PA meaning PA associated with treatment for a prior known PitNET: neurosurgery, pituitary radiotherapy, and medication for hormonally active PitNETs, for instance, dopamine analogs  for prolactinomas and somatotropinomas, respectively, somatostatin analogs , and growth hormone (GH) receptor antagonist pegvisomant for somatotroph PitNETs.According to our methodology, we identified 194 original papers that included 165 case reports, 5 case series, 22 retrospective studies, one case–control study, and one prospective study. Overall, 1452 patients with PA were included . In accordance with medical literature, we found a male predominance . The mean age of patients was 50.52 years, the youngest was 9, and the oldest was 85 years ,221,222 Sudden headache was the most frequent symptom and occurred in more than two-thirds of patients.  HeadacheOther common symptoms include nausea and vomiting, either with a neurological or endocrine component  ,208,217.Another important clinical finding is meningism, a crucial clue for differentiating between two life-threatening conditions: PA presenting as aseptic meningitis and bacterial meningitis. PA mimics neurological conditions, such as bacterial ,119,168 PA may associate cerebral ischemia through either extrinsic compression or vasospasm, leading to neurological deterioration  in patients who suffered from acute ischemic stroke following PA ,146,199.PA-associated visual disturbances include decreased visual acuity in most cases ,190,196.Endocrine features in subjects admitted for PA include PitNETs-associated hormonal excess, even though most patients were nonfunctioning tumors, respectively, tumor- or PA-caused hypopituitarism . In terms of clinical presentation, Cushingoid features (corticotroph PitNET) are reported in 5 studies (less than 0.005% of the patients): two males of 30, respective 33 years ,186, a cOther signs and symptoms at PA presentation include lactotroph PitNET-associated galactorrhea ,174,183;In terms of the PitNET stain profile  non-functional type was followed by somatotroph PitNETs ,192,217,Our decade-based analysis showed that high blood pressure may be regarded as the most frequent co-morbidity (or risk factor) followed by diabetes mellitus in individuals admitted for PA.  Two caseEnterobacteriaceae in patients with PA [Infectious triggers were also found and include pituitary fungal infection , dengue  with PA .Traumatic causes are identified; for instance, head trauma ,160,204,Anticoagulation ,195,198 Oral contraceptives may contribute to PA . KobayasIatrogenic components may include diagnostic tests and procedures: dexamethasone suppression test , clomiphOther therapeutic procedures include the intravitreal injection of vascular endothelial growth factor inhibitor , autologTwo case reports presented individuals with PA caused by exposure to high altitudes (the first case was published in 2012). Both subjects were 29-year-old males without underlying pituitary conditions who ascended slowly to altitudes of over 4500 m. The initial diagnosis was acute mountain sickness in both cases. However, due to low blood pressure and findings of adrenal insufficiency, PA was suspected, and later MRI scans confirmed PA. Neither patient displayed visual disturbances . The manOf note, two unusual triggers are polysubstance abuse  and longThe management of the patients recognized with PA is summarized in Conservative management ,219,220 A few cases under the “wait and see” approach were later referred to TSS due to worsening conditions: hematoma expansion  or suddeWe identified three clinically relevant studies that compared conservative management versus TSS in terms of evolution ,160,168.We mention some isolated reports with uncommon management such as radiotherapy for a subject diagnosed with a null cell tumor and a gonadotroph PitNET ; palliatA large number of patients required hormonal replacement due to PA-associated hypopituitarism manifested as hypocortisolism which is the most important aspect in terms of an immediate life-threatening approach ,169,208,As mentioned, some small studies evaluated the outcome in terms of conservative versus neurosurgical management. A retrospective study (N = 46 patients with PA) showed that individuals with non-severe neuro-ophthalmological deficits were treated conservatively (N = 27), whereas the patients with a pituitary apoplexy score (PAS) ≥4 were treated surgically (N = 19); the only statistically significant difference regarding the outcome was the higher rate of hormonal deficits in the second group . AnotherThe timing of surgery was also taken into consideration by some studies, as a contributor to PA outcome. A study conducted by Rutkowski M et al. (N = 32 patients with acute PA who underwent TSS) included two groups depending on surgery timing: within 72 h of symptom onset and after 72 h; the second group had a statistically significant higher prevalence of hypopituitarism at presentation. However, in terms of hypopituitarism and visual dysfunction recovery, the outcome was similar .The spontaneous resolution of PitNET through PA was reported with a favorable outcome ,154,220.Fatal outcome surrounding PA was registered as an early event, for instance, within 48 h  or afterOf note, we identified through our analysis a single case of PA in the transgender population: a 46-year-old transgender male under testosterone therapy for 3 years who was admitted for severe headache, central hypocortisolism, and hypothyroidism. IGF-1 (insulin-like growth factor) levels, however, were high. The patient was diagnosed with somatotroph PitNET-associated PA and received surgical treatment with normalization of IGF-1 and improvement of secondary diabetes mellitus. Particularly, testosterone therapy in this situation may mask acromegaly features  please .An unusual case of “pneumo-apoplexy” was described by Singhal A et al.; a 65-year-old female had a PA-associated hemorrhage accompanied by pneumosella and manifested as rhinorrhea as well as classical symptoms of PA including headache and visual loss. The patient needed flap replacement of the nasoseptal defect .“Recurrent” apoplexy was reported by Hosmann A et al. in 4 out of 76 patients (5.3%) after initial neurosurgery. Potential factors include residual post-operatory tumor, cavernous sinus invasion of PitNET, and ophthalmoplegia . HoweverSome patients presented “subacute” PA, with little to no symptoms, thus the importance of imaging assessments like MRI scans that point out infarction or hemorrhage . The terPA is an emergency that typically presents a sudden and severe headache and visual symptoms; however, subacute cases or those without headaches should not be missed. The most frequent cause is hemorrhage or ischemia in a nonfunctioning pituitary adenoma, but hormonally active PitNET may embrace a PA scenario. Middle-aged males are affected with the highest frequency, but both pediatric and elderly cases are shown in The optimal treatment approach remains debated, but the main treatment options are TSS or conservative management. Due to possible complications from surgery, as well as a higher rate of pituitary insufficiencies after surgical treatment when compared with conservative management, careful evaluation is necessary. The individual multidisciplinary decision is mandatory. Surgical management should be reserved for patients with visual impairment due to cranial nerve palsies and optic chiasm compression, or patients with other neurological deficits. Conservative treatment is usually an adequate approach for stable patients with mild and stationary visual deficits and without further neurological impairments. When choosing conservative management, the risk of PA recurrence should also be taken into account. .In terms of outcome, headaches and visual disturbances may resolve following both conservative and surgical treatment. Patients can present different degrees of anterior hypopituitarism and diabetes insipidus. Factors for a worse prognosis may be the presence of a large macroadenoma and an ischemic type of apoplexy. PA is a condition that can lead to a favorable outcome with the remission of symptoms and underlying pituitary disorder in some patients, whereas for others it can be life-threatening and invalidating when fatal cases are reported . Specific algorithms of management are still necessary.To our knowledge, this is the largest analysis of published cases concerning spontaneous PA (outside pregnancy and COVID-19 infection). A timeline of published papers from 2012 to 2022 according to our methodology is displayed below. The largest studies addressing individuals with PA included 109, 97, and 87 subjects, respectively ,221,222.Abbreviations: N represents the number of patients included in studies with at least 10 subjects with PA per article . The modern approach of these tumors massively takes into consideration the role of immunohistochemistry for mainly five elements: PIT1, TPIT, SF-1, GATA3, and ERα in order to profile PitNET subtypes. The major changes are, a part form this new terminology: null cell tumors and unclassified pluri-hormonal tumors as a subtype of PitNETs with negative staining for transcription factors; “metastatic” PitNET replaced “metastatic carcinoma” that should be differentiated from a neuroendocrine carcinoma; immature (formerly “silent”) or mature PIT1-lineage tumor are determined based on PIT1 immunostaining; and mammosomatotroph, acidophil stem cell tumors in addition to mixed somatotroph/lactotroph tumors are distinct types with respect to PIT-1 lineage of PitNET ,225,226 We acknowledge that the current review did not follow the PRISMA guidelines for systematic review and may have missed some studies because only PubMed was used for the literature search.PA in PitNETs still represents a challenging condition requiring a multidisciplinary team from first presentation to short- and long-term management. Controversies involve the specific panel of risk factors and adequate protocols with concern to surgical decisions and their timing. The present decade-based analysis, to our knowledge the largest so far on published cases, confirms a lack of unanimous approach and criteria of intervention, a large panel of circumstantial events and potential triggers with different levels of statistical significance, in addition to a heterogeneous clinical picture  and a spectrum of evolution that varies from spontaneous remission and control of PitNET-associated hormonal excess to exitus. Awareness is mandatory. A total of 25 cohorts have been published so far with more than 10 PA cases/studies, whereas the largest cohorts enrolled around 100 patients. Further studies are necessary.


The research was aimed to evaluate the subclinical left ventricular (LV) myocardial systolic dysfunction in T2DM patients with or without hypertension (HT) by global and segmental myocardial work (MW).A total of 120 T2DM patients (including 60 T2DM patients with HT) and 70 sex- and age- matched normal controls were included. The global and segmental variables of work index (WI), constrictive work (CW), waste work (WW), work efficiency (WE), and CW/WW were analysed by non-invasive pressure-strain loop. Receiver operating characteristic (ROC) analysis was performed for detection the subclinical LV systolic dysfunction in T2DM patients with and without HT.The global work index (GWI), global CW (GCW), global WE (GWE), and GCW/global WW (GWW) of T2DM and T2DM patients with HT were significantly lower than normal controls (p < 0.05). The WI, CW, WE, and CW/WW of the LV anterior wall in T2DM and T2DM patients with HT were significantly lower when compared with those of the normal controls (p < 0.05). ROC analysis showed that the value of area under the curve (AUC) in combined GWI, GCW, GWE, and GCW/GWW was significantly higher than the AUCs of the individual indices (p < 0.05).MW can non-invasively and accurately evaluate subclinical global and segmental LV myocardial systolic dysfunction in T2DM patients with and without HT. Regulating total cholesterol levels and controlling blood pressure in T2DM patients with and without HT might reduce the impairment of LV myocardial systolic function. With the growth of the population and increased longevity, non-infectious chronic diseases (NCDs) are still the main causes of poor health worldwide. In a report released by the World Health Organization in 2022 , as one Myocardial work (MW) estimation has been validated as a novel, non-invasive method for constructing the LV pressure-strain loop (PSL) area, with good correlation with directly measured MW, and it is able to reflect the systolic and metabolic capacity of the myocardium , 10. PreThe study population included 165 T2DM patients who had already been diagnosed or were diagnosed during hospitalization and 83 T2DM patients who were simultaneously diagnosed with HT or had a history of HT. The diagnostic criteria for T2DM conformed to the latest guidelines : A1C ≥ 6An ultrasound machine  was used by senior sonographers to perform standard 2-dimensional transthoracic echocardiography. 40–60 frames of standard images in three cardiac cycles at the apical two-, three- and four- chamber views were collected, and the electrocardiogram was connected while images were collected. Proprietary software  was used to store images and perform offline analysis.Left atrium diameter (LAd), interventricular septum thickness diameters (IVSd), LV diameter (LVd) and LV posterior wall thickness diameters (LVPWd) were measured from the parasternal long-axis views in the end-diastole period .Maximal The displacement waveform of the mitral annulus during systole was measured from M-mode echocardiography in apical four-chamber views, with the distance between the peak point and the nadir as the magnitude of the mitral annular plane systolic excursion (MAPSE) . LV end-The image analysis in this study was usually performed offline by two senior sonographers using EchoPAC 203. The regions of interest were automatically delineated in the acquired standard apical four-, two- and three-chamber views by STE, and if necessary, the endocardial borders were manually adjusted to better track myocardial motion. LV GLS was derived based on averaging the peak strain of 17 segments from three apical views. The ejection period was defined according to the open cut points of the mitral and aortic valves. LV PSL was constructed by non-invasive measurement of LV systolic pressure combined with LV GLS.The area of LV PSL is equal to the LV GWI. During systole, the work done to promote the shortening of the myocardium is constructive work (CW), and myocardial work performed during elongation is waste work (WW). At isovolumetric diastole, the work contributing to myocardial lengthening is the CW, and the work of myocardial shortening is defined as the WW.The basal, mid, and apical sections of the myocardium were confluent to generate six segments  to evaluate segmental differences in MW.All patients and normal controls underwent blood collection on the day of image collection, and blood biochemical parameters were analysed by the Department of Laboratory Medicine. The glycated haemoglobin A1c (HbA1c) of patients was obtained through HLC-723 G11 (Tosoh Bioscience) and its corresponding kit. The total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), blood urea nitrogen (BUN), and serum creatinine (SCR) concentrations of patients were obtained through Roche Cobas 8000 and these corresponding kits.2 test were applied. Univariate regression analysis was first used to evaluate the relationship between traditional echocardiographic or clinical parametersand global and segmental myocardial work parameters. Each relevant parameter with a p value of < 0.20 was included in the multivariate regression analysis. The parameters of MW in the normal controls were defined as normal, and the corresponding indexes in T2DM patients with and without HT were defined as abnormal. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the sensitivity and specificity of MW in evaluating subclinical LV myocardial systolic dysfunction in T2DM patients with and without HT. Reproducibility was tested by intra- and intergroup correlation coefficient analysis.SPSS statistical software, version 23.0 , was used for the statistical analysis of all data. Statistical significance was indicated by a p value of < 0.05. The Shapiro‒Wilk test was used to test whether the data conformed to normal distribution. Continuous variable data are presented as the mean ± SD when normally distributed and the median (interquartile range) when not normally distributed. Absolute values and percentiles were used to represent categorical data. When comparing normal controls, T2DM patients, and T2DM patients with HT, one-way analysis of variance (ANOVA), the Kruskal‒Wallis test, or the xThe clinical parameters of the study cohort are shown in Table Traditional echocardiographic parameters of the study cohort are shown in Table trend < 0.05). GWE (p = 0.002) and GCW/GWW (p = 0.004) appeared significantly lower in T2DM patients with HT than in normal controls, and both showed a decreasing trend (ptrend < 0.05). Although the divergences in GWW among the three groups were not significant (p = 0.064), the overall value showed an increasing trend (ptrend = 0.003).The global MW parameters of the study cohort are shown in Table As shown in Table Multivariate regression analysis was applied to appraise the independent effects of the above indicators on GCW. TC (p = 0.040), SBP (p < 0.001), and MAPSE (p < 0.001) were were independently associated with GCW in T2DM patients with and without HT.An ROC curve was constructed to analyse whether MW could accurately evaluate subclinical LV myocardial dysfunction in T2DM patients with and without HT Table . The senThe intraclass correlation coefficients (ICCs) for GWI, GCW, GWW, GWE and GCW/GWW were 0.96 , 0.94 , 0.94 , 0.89  and 0.88 , respectively. The interobserver ICCs were 0.94  for GWI, 0.91  for GCW, 0.88  for GWW, 0.86  for GWE and 0.86  for GCW/GWW.The segmental MW parameters of the study cohort are shown in Table The present study provides the followingfindings: (1) T2DM with and without HT patients have subclinical global and segmental LV myocardial systolic dysfunction, and the impairment of anterior wall is more significant. (2) TC, SBP, and MAPSE were independent influencing factors for GCW in T2DM patients. (3) The combination of GWI, GCW, GWE, and GCW/GWW was better than GWI, GCW, GWE, and GCW/GWW alone in evaluating subclinical LV myocardial systolic dysfunction in T2DM patients with and without HT .Micro- and macrovascular lesions that cause myocardial ischaemia  or diabeMW as a novel technique has been used in recent studies to evaluate the effects of cardiovascular disease on myocardial systolic function. Edwards et al.  found thTherefore, in the present study, after applying MW estimation to evaluate LV myocardial systolic function in T2DM patients with and without HT, we found that GWI, GCW, GWE, and GCW/GWW were significantly impaired compared with those in normal controls. In addition, from the normal controls to T2DM patients with HT, GWE and GCW/GWW showed a decreasing trend, and GWW showed an increasing trend. Myocardial work efficiency is derived indirectly from the ratio of constructive and wasted myocardial work . GCW/GWWAdditionally, in the present study, we evaluated the segmental differences in MW in T2DM patients and T2DM patients with HT compared with normal controls to identify the negative effects of myocardial segments in T2DM patients with and without HT. The impairment of anterior wall was more evident, and the lateral, inferior, posterior, and septum were also impaired to various degrees, but no significant impairment was observed in the anteroseptal wall. Segmental myocardial systolic dysfunction may be related to abnormal lipid metabolism in T2DM patients . On the Global and segmental analysis of MW in T2DM patients with and without HT can be more convenient and rapid for helping clinicians identify patients with global and segmental myocardial systolic dysfunction at subclinical stages with preserved LVEF. Therefore, treatment can be administered at an early stage, leading to fewer cardiovascular complications. We incorporated GCW/GWW, a new evaluation parameter, based on the original GWI, GCW, GWW and GWE. Thus, a more intuitive evaluation constructs a gain/loss relationship between work and waste. TC was independent influencing factor for the development of impaired GCW in T2DM patients with and without HT, suggesting that T2DM patients need control blood lipids to reduce the toxic effects of lipids on cardiomyocytes, also T2DM patients should control their blood pressure. These findings could be used to derive additional protocols and provide value when MW evaluation is applied to other cardiovascular diseases. In addition, it was concluded in ROC curve analysis that evaluation with a combination of the above four indices of subclinical LV myocardial systolic dysfunction was significantly better than that of single index evaluation.MW can non-invasively evaluate subclinical global and segmental LV myocardial systolic dysfunction in T2DM patients with and without HT. TC and SBP were independent influencing factors for GCW in T2DM patients with and without HT. Regulating total cholesterol levels and controlling blood pressure in T2DM patients with and without HT might reduce the impairment of LV myocardial systolic function.There are still some limitations in the present study. First, patients with poor image quality due to obesity, smoking, etc., were excluded, so this exclusion criterion may be biased for different operators. Furthermore, the present study was a single-centre study, and multicentre large sample studies are needed to further provide reference value for this finding.


Atrial fibrillation is the most common arrhythmia encountered in clinical practice affecting both patients’ survival and well-being. Apart from aging, many cardiovascular risk factors may cause structural remodeling of the atrial myocardium leading to atrial fibrillation development. Structural remodelling refers to the development of atrial fibrosis, as well as to alterations in atrial size and cellular ultrastructure. The latter includes myolysis, the development of glycogen accumulation, altered Connexin expression, subcellular changes, and sinus rhythm alterations. The structural remodeling of the atrial myocardium is commonly associated with the presence of interatrial block. On the other hand, prolongation of the interatrial conduction time is encountered when atrial pressure is acutely increased. Electrical correlates of conduction disturbances include alterations in P wave parameters, such as partial or advanced interatrial block, alterations in P wave axis, voltage, area, morphology, or abnormal electrophysiological characteristics, such as alterations in bipolar or unipolar voltage mapping, electrogram fractionation, endo-epicardial asynchrony of the atrial wall, or slower cardiac conduction velocity. Functional correlates of conduction disturbances may incorporate alterations in left atrial diameter, volume, or strain. Echocardiography or cardiac magnetic resonance imaging (MRI) is commonly used to assess these parameters. Finally, the echocardiography-derived total atrial conduction time (PA-TDI duration) may reflect both atrial electrical and structural alterations. The patalities,  autonomiion and,  structurmodeling . The evomodeling . On the modeling . Lifestymodeling ,12,13,14Structural remodelling refers to the development of atrial fibrosis, as well as to alterations in atrial size and cellular ultrastructure. The latter includes myolysis, the development of glycogen accumulation, altered Connexin expression, subcellular changes, and sinus rhythm (SR) alterations .Atrial fibrosis is the most important feature of structural remodeling in AF, although many inconsistencies in the association between fibrosis and AF are encountered . HoweverAtrial fibrosis may promote arrhythmogenesis in many ways. First, it separates atrial fibers in the longitudinal direction and creates significant conduction barriers. Such conduction barriers are responsible for significant conduction delays or blocks that induce re-entry . Second,Connexins are specialized hemichannel subunit proteins that maintain the low-resistance intercellular coupling and, therefore, the myocardial electric continuity. Connexin (Cx)43 and Cx40 are important for the atrial gap junctions . Cx43 isThe role of inter-atrial conduction in the development and management of AF is incompletely clarified ,25. ScarThe associations between the presence of interatrial block (IAB) and structural remodeling of the atrial myocardium in the tissue, cellular, or subcellular levels are consistently shown . IAB comAging is associated with conduction slowing and frequent conduction blocks, mainly at the BB and right atrium (RA) . Low volRecent studies have postulated the depressive effect of stretch on atrial conduction, focusing on the prolongation of interatrial conduction time when atrial pressure is acutely elevated . StretchP wave parameters can undergo changes under various normal physiological conditions but more frequently when atrial pathology is present. These alterations can be easily detected on a standard 12-lead electrocardiogram (ECG) and can be measured manually or automatically .Advanced IAB has been associated with the development of AF or atrial flutter. Other P wave parameters, such as the P wave axis, P wave voltage, P wave area, and P terminal force in V1, have also been considered risk markers of AF .A P wave duration ≥ 120 ms is considered abnormal and is a criterion for partial IAB, that is a conduction delay between RA and LA through the BB. In the case of advanced IAB, the LA is retrogradely activated via muscular bundles located close to the atrioventricular junction. In advanced IAB, increased P wave duration is accompanied by P wave morphology changes in leads II, III, and aVF . P wave duration independently predicts AF recurrence after radiofrequency (RF) ablation. The risk of AF recurrence increases substantially with a P wave duration > 150 ms .P wave axis values between 0° and 75° are considered normal. The abnormal P wave axis increased the risk of AF by 17% .P wave voltage ≤ 0.1 mV in lead I is considered abnormal. Abnormally decreased P wave amplitude in lead I is associated with post-ablation AF recurrence .Abnormal P wave area is defined as ≥4 ms×mV and has been considered a marker of left atrial enlargement (LAE) . P wave The posterior displacement of the LA in LAE is manifested on the ECG with a longer P wave duration and a more pronounced negative component of the P wave in V1 .P wave dispersion is defined as the difference between the maximum and the minimum P wave duration in any of the 12 ECG leads. Higher values of P wave dispersion have been associated with a higher incidence of “lone” AF and the appearance of post-cardioversion AF recurrences .Premature atrial contractions (PACs) may trigger AF initiation. PACs commonly originate from the pulmonary veins (95%) and scarcely from the superior vena cava and the coronary sinus, especially when associated with the persistence of the left superior vena cava (5%). Although pulmonary vein isolation (PVI) is a satisfactory ablation strategy, AF recurrences frequently occur after a successful PVI. The main reason for post-ablation AF recurrences is PV reconnection . Progression from paroxysmal to more persistent forms of AF indicates the evolution from a trigger-mediated to an electro-pathology-mediated initiation and maintenance of the arrhythmia. Several electrophysiological characteristics have been proposed as indicators of AF-related electro-pathology at both atria and the BB.The presence of low voltage areas (≤0.5 mV) in LA during high-density bipolar voltage mapping indicates the presence of fibrosis, is considered responsible for the initiation and maintenance of AF  Figure .Modern ablation strategies may combine PVI with LA substrate modification targeting low-voltage zones in the LA . Rolf etUnipolar electrograms (EGMs) provide additional information on wavefront progression. Unipolar voltages are higher in the LA compared to the RA in patients with persistent AF during CS pacing . UnipolaFractionated EGMs are associated with slow conduction. However, they may appear during SR in areas characterized by normal voltages and cardiac conduction velocity .The presence of asynchronous activation of the atrial endocardial and epicardial layers may lead to focally propagating fibrillation waves . UnipolaIsochronal maps in isopotential lines are drawn over a fixed time interval and are used to estimate conduction velocity. Conduction velocity has been shown to be slower in patients with AF . MoreoveAtrial remodelling is assessed using echocardiography or cardiac MRI to measure LA size and function. Both are well-established predictors of AF-related outcomes.Atrial dilatation’s relationship to the incidence of AF was first described in mitral valve disease patients . Twenty A change in atrial structure and function is the background of atrial remodelling, which results in left atrial enlargement ,73. On tIt is well established that LA diameter is an independent predictor of AF recurrence post-PVI . AlthougAtrial contractile dysfunction, as assessed by echocardiography, is correlated with the duration of AF. After a 2-week period of AF and restoration of SR, 24 h was the time for the recovery of atrial contractile function. On the other hand, it took more than 1 month for recovery, while AF lasted more than 6 weeks ,86. A ne2+ inward current (ICaL) [CaL induced the atrial contractile dysfunction noted during the first 5 days of AF. Interestingly, after the restoration of SR, atrial contractility recovered completely within 3 days. An increase in compliance and the diameter of the atrium was noted early, during the first days of AF, following the same time course as the loss of contractility, and were fully reversible within two days of SR. Loss of atrial contractility is one of the mechanisms of atrial dilatation during prolonged AF, while the stretch of the atrial wall might lead to the elongation of the collagen fibers. Cellular hypertrophy and possible synthesis of new collagen fibers may also contribute as well [In another animal model of AF , changest (ICaL) . As a re as well .2DS2-VASc scoring [LA reservoir strain, as a surrogate of LA compliance, is a predictor of AF-related outcomes, including stroke ,95. In a scoring . Both LA scoring ,98. In a scoring ,100. Fin scoring .Total atrial conduction time (PA-TDI duration) is an echocardiography-derived parameter that reflects LA electrical and structural changes. By obtaining a Tissue-Doppler Imaging (TDI) tracing of the lateral LA wall just below the mitral annulus level in the apical 4-chamber view, PA-TDI duration is calculated by measuring the time interval from the P-wave onset on the ECG to the peak of the A’-wave . This is2DS2-VASc score performance [The correlation between PA-TDI duration and the degree of right atrial appendage fibrosis was presented by Müller et al. in a histological validation study . PA-TDI formance . Anotherformance . Lastly,formance . Structural remodeling encounters alterations in atrial tissue properties, size, and cellular ultrastructure that underline the pathophysiological basis of AF. Electrical correlates of conduction disturbances include relative abnormalities in electrocardiographic or electrophysiological characteristics of vulnerability to AF. Finally, echocardiography- or MRI-derived functional correlates of conduction disturbances may further enhance AF prediction.