ND) group and an IVS displacement (IVSD) group according to IVS morphology, as observed on short-axis cine CMR images. Additionally, age-matched healthy volunteers were included as the health control (HC). Temporal parameters, IVS displacement, ventricular volume and functional parameters were obtained by CMR, and pulmonary hemodynamics were obtained by RHC. The risk stratification of the PH patients was also graded according to the guidelines. Results: A total of 70 subjects were included, consisting of 33 IVSD patients, 15 IVSND patients, and 22 HC patients. In the IVSND group, only the right ventricle ejection fraction (RVEF) was decreased in the ventricular function, and no temporal change in the cardiac cycle was found. A prolonged isovolumetric relaxation time (IRT) and shortened filling time (FT) in both ventricles, along with biventricular dysfunction, were detected in the IVSD group (p < 0.001). The IRT of the right ventricle (IRTRV) and FT of the right ventricle (FTRV) in the PH patients were associated with pulmonary vascular resistance, right cardiac index, and IVS curvature, and the IRTRV was also associated with the RVEF in a multivariate regression analysis. A total of 90% of the PH patients in the IVSD group were stratified into intermediate- and high-risk categories, and they showed a prolonged IRTRV and a shortened FTRV. The IRTRV was also the predictor of the major cardiovascular events. Conclusions: The temporal changes in the cardiac cycle were related to IVS displacement and mainly impacted the diastolic period of the two ventricles in the PH patients. The IRT and FT changes may provide useful pathophysiological information on the progression of PH.Background: Pulmonary hypertension (PH) is known to alter the biventricular shape and temporal phases of the cardiac cycle. The presence of interventricular septal (IVS) displacement has been associated with the severity of PH. There has been limited cardiac magnetic resonance (CMR) data regarding the temporal parameters of the cardiac cycle in PH. This study aimed to quantify the temporal changes in the cardiac cycle derived from CMR in PH patients with and without IVS displacement and sought to understand the mechanism of cardiac dysfunction in the cardiac cycle. Methods: Patients with PH who had CMR and right heart catheterization (RHC) examinations were included retrospectively. Patients were divided into an IVS non-displacement (IVS The right ventricle (RV) and left ventricle (LV) work within a distensible pericardium and are connected to each other through the interventricular septum (IVS), which shares myocardial fibers with both ventricles and accommodates the interactions between the two ventricles . TherefoIncreased pulmonary arterial pressure (PAP) can lead to prolonged and inhomogeneous RV contraction and has been associated with negative ventricular–ventricular interactions in pulmonary hypertension (PH) ,4. ThereCardiac magnetic resonance (CMR) imaging is a non-invasive, robust diagnostic follow-up tool used for PH patients . Cine CMThe goal of this study was to quantify the temporal changes in the cardiac cycle in PH patients with different IVS shapes and their relationship with the cardiac function using CMR, and to understand the mechanism of cardiac dysfunction in the cardiac cycle.D) group, while the PH patients without IVS displacement were classified as the IVS non-displacement (IVSND) group. Additionally, 22 age-matched healthy volunteers with no evidence of any heart diseases also underwent CMR examination and were included as the health control (HC) group , as defined by the European Society of Cardiology , but whoC) group . The stuCMR was performed on a 3.0 T MR scanner  with an 8-channel cardiac coil, using a vector-cardiographic method for electrocardiogram gating. The short-axis cine CMR images (slice thickness = 8 mm), 4-chamber cine images (slice thickness = 6 mm), and LV and RV outflow tracts (slice thickness = 6 mm) were acquired using fast imaging employing steady-state acquisition (FIESTA) during breath-holds. The acquisition parameters were as follows: 20 frames per cardiac cycle, repetition time 3.40 to 3.60 ms, echo time 1.50 to 1.60 ms, flip angle = 45°, bandwidth = 125 KHz/pixel, field of view = 35 cm × 35 cm, matrix = 224 × 224, and NEX = 1.IVS) and curvature ratio (CR). The RV and LV function analysis was also performed using the short-axis cine CMR images. The RV and LV endocardial and epicardial borders were automatically traced with manual adjustments to obtain the end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV) and ejection fraction (EF). The papillary muscles and trabeculae were included in the ventricular cavity volume. The myocardial mass (MM) was calculated by multiplying the volume of the ventricular myocardium in the end-diastolic phase with its density (1.05 g/cm3). The ventricular mass index (VMI) was calculated by dividing the RVMM by the LVMM. All the cardiac functional parameters were divided by the specific body surface area (BSA) for normalization and recorded as the end-diastolic volume index (EDVI), end-systolic volume index (ESVI), stroke volume index (SVI) and myocardial mass index (MMI), respectively.The CMR image analysis was performed with Report Card 3.7 on GE Advantage Workstation 4.6. The analysis of the IVS morphology was performed using the short-axis cine CMR images, as previously described in the literature ,13,14, iThe opening and closure of the aortic valves, pulmonary valves, mitral valves and tricuspid valves were reviewed using the cine CMR images. The aortic valves and pulmonary valves were reviewed using the outflow tract cine images of the LV and RV, respectively. The mitral valves and tricuspid valves were observed using the 4-chamber cine view. The opening time and closure time of the valves were normalized and recorded as the percentage of the R-R interval. The cardiac cycle was composed of an isovolumetric relaxation phase, a filling phase, an isovolumetric contraction phase and an ejection phase. The durations of the four phases were calculated as follows :To assess the inter-observer and intra-observer reproducibility of the temporal parameters of the cardiac cycle, 18 (26%) PH patients were selected randomly and re-examined independently by the two readers . For the intra-observer reproducibility, one observer (FY) repeated the measurements four weeks later. The intra-class correlation coefficient was used to assess the reproducibility.In line with the risk assessment instrument from the abbreviated version of the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) risk stratification strategy [All the PH patients were followed up with a census date of 12 January 2021. The designed primary endpoint was defined as major cardiovascular events (MACE), which included hospitalization for heart failure, lung transplantation, malignant ventricular arrhythmia and death.ND and IVSD. The categorical variables were presented as frequencies (%) and compared using Fisher’s exact test. The correlation between the parameters was calculated with Spearman’s correlation coefficient. Multivariable stepwise regression analysis was used to explore the factors associated with RVEF. Each variable with a significant association (p < 0.05) in the univariate analysis was introduced into the regression model. The differences in the ventricular function and the temporal parameters between the low-risk group and the intermediate- and high-risk groups were tested by the Mann–Whitney U test. The univariable and multivariable Cox regression models included demographic factors, clinical factors, laboratory tests, and RHC and CMR variables . All the analyses were two-sided, and p-values of <0.05 were considered to be statistically significant.SPSS 23.0 was used for all the statistical analyses. All the continuous variables were presented as medians and interquartile ranges (IQR) when the variables were not normally distributed. The Kruskal–Wallis one-way ANOVA test, with Bonferroni correction post hoc analysis, was used to compare the continuous variables among the three groups of HC, IVSND group, the IVSD group and the HC group. The IVSD group had significantly decreased 6MWD and increased NT-proBNP and WHO FC levels. The HR was significantly faster in the IVSD group than in the IVSND group (p < 0.05) and in the HC group (p < 0.001). No significant differences between the IVSND group and the IVSD group in the proportion of PH subsets (p > 0.05) were observed. The mPAP, PVR, CI and mRAP were higher in the IVSD group than in the IVSND group (p < 0.05).The clinical characteristics of the subjects are presented in D group had significantly decreased CIVS and CR when compared with the IVSND group and the HC group . The RVEF was the only decreased parameter in the IVSND group compared with the HC (p < 0.05). While there was no significant difference in the RVSVI among the three groups (p > 0.05), among the LV parameters (D patients (p < 0.001). There was no significant difference in the LVEF among the three groups (p > 0.05) (D group were increased (p < 0.01), but the LVMMI showed no difference.rameters b, the LV > 0.05) . The RVMND and HC groups.D showed no difference in the PO, PC, ETRV and ICTRV in terms of the RV-pulmonary artery system, while this group showed a delayed TO, an advanced TC, a longer IRTRV and a shorter FTRV (p < 0.001). With regards to the LV-aorta system, although both the AO and the AC were advanced, the ETLV and the ICTLV showed no differences in the IVSD group. The IVSD group showed no differences in the MO, while showing an advanced MC, a longer IRTLV and a shorter FTLV (p < 0.001).Compared with the HC group, the IVSD and IVSND, a longer IRTRV and shorter FTRV were detected along with a delayed TO in the IVSD group (p < 0.05) (C (p < 0.05).Comparing the two groups of IVS < 0.05) . HoweverThe intra- and inter-observer reproducibility results using intra-class correlation coefficients are shown in the RV was significantly correlated with the PVR, CI and CIVS . The FTRV was significantly correlated with the mPAP, PVR, CI and CIVS . There were significant correlations between some ventricular functional parameters and mPAP, PVR, CI and CIVS, respectively (p < 0.05) (The IRT < 0.05) .RV, LVEF and PVR were significantly associated with the RVEF  . < 0.05) . PatientRV, CR and mPAP were associated with the MACE. The multivariable analysis showed that the IRTRV and mPAP were the significant predictors of the MACE (Twelve patients (25%) with PH died during the median follow-up period of 62 months (interquartile range: 38–67 months). The univariate Cox proportional hazards regression analysis of all the PH patients showed that age, WHO FC, 6MWD, IRTthe MACE .RV may have the potential to predict the prognosis for PH patients. However, the PH patients without IVS displacement showed no temporal variations in the cardiac cycle.This cardiac MR study has provided detailed information about the temporal variations in the cardiac cycle in the progression of PH patients. The main variations were in the diastolic period, and the PH patients with IVS displacement had a longer IRT and shorter FT for both the RV and LV, and a prolonged IRT and shortened FT of the RV were associated with the RV afterload. Additionally, the IRTIncreased PVR and elevated PAP are the main factors responsible for PH, leading to vascular remodeling and cardiac remodeling . During IVS and CR were both reduced in the IVSD patients. The RVEDVI, RVESVI and RVMMI were significantly increased and the RVEF was further decreased in the IVSD patients compared with those of the IVSND patients and HC patients. The LVEDVI, LVESVI and LVSVI were decreased with the IVS displacement and LV compression.Although increased mPAP and PVR reflect the severity of PH, increased mPAP and PVR do not reflect an adverse ventricular–ventricular interaction, interventricular pressure gradient and interventricular septal motion directly . The incFurthermore, RV pressure loading influences not only the IVS morphology but also the temporal phases of the cardiac cycle . In geneRV and shortened FTRV in the IVSD patients. In PH patients with IVS displacement, the increased RV pressure and inefficient RV diastolic function could result in a prolonged IRTRV, which could in turn decrease the intraventricular pressure. Moreover, increased RV pressure would promote the closure of the tricuspid valve and shorten the FTRV accordingly. An increased afterload would reduce the myocyte velocity and prolong the myocyte shortening. Thus, RV actin-myosin cross-bridge cycling may result in a stiffer myocardium near the end of the ventricular ejection, prolonging the IRT and hampering the early relaxation [RV was prolonged in PH patients when compared with the controls, resulting in a noticeable delay in atrioventricular opening [RV then impedes its filling, which has an essential impact on the RV systolic function [With respect to the pulmonary artery-RV system, our study identified delayed To, advanced Tc, prolonged IRTlaxation . The IRT opening . The shofunction .D patients displayed advanced Mc, prolonged IRTLV and shortened FTLV. This was linked to IVS displacement. The increased RV pressure causing the RV dilatation and IVS flattening or even bowing to the LV would result in a smaller LV cavity, which leads to the LV underfilling and reduction in the LVSV. RV dilatation and IVS displacement had a further deleterious effect on ventricular interactions [With respect to the LV-aorta system, the IVSractions . Under tractions ,21,22,23RV, FTRV and some of the cardiac functional parameters  were associated with PVR, CI and CIVS. Additionally, the IRTRV, LVEF and PVR were associated with the RVEF in the multivariate regression analysis. All these findings indicate that the IVS displacement and increased RV afterload were not the only factors related to ventricular dysfunction. The temporal variations of both the IRTRV and FTRV in the cardiac cycle may also be associated with an IVS morphological abnormality and impaired ventricular function, especially in the case of the IRTRV.Our findings also showed that IRTRV and shortened FTRV. These findings indicate that the temporal variations of the IRTRV and FTRV in cardiac cycle could also inform the risk stratification of PH patients. Moreover, the multivariable Cox proportional hazards regression analysis showed that the IRTRV was the significant predictor of the MACE. This indicates that the IRTRV might serve as a potential prognostic factor for PH patients.Guidelines on the diagnosis and treatment of PH, published by the European Society of Cardiology and European Respiratory Society, state that the overall treatment goal for patients with PH is to achieve a low-risk status, which is usually associated with good exercise capacity, good quality of life, good RV function and a low-mortality risk . The maiRV, and shortened FTRV indicate RV failure in patients with precapillary-PH, and, more seriously, predict clinical worsening [By applying the current methods in the clinics, we can not only evaluate the function and morphology of the ventricles, but also provide extra temporal information for PH patients, without introducing additional CMR sequences and scanning times. This pathophysiological information may give the doctors a profound understanding of both the progression of PH and the interaction between the ventricles, offering help in the guidance of the treatment strategy for individuals with PH. IVS displacement, prolonged IRTorsening . On the orsening . The temorsening . The finThis study has several limitations. Firstly, this is a single-center study with a small sample size. The current results and discoveries should be further validated using a large PH population. Next, although the four phases in the cardiac cycle were clearly set out in this study, the pilot temporal parameter method, which used CMR cine data with images including 20 frames from multiple cardiac cycles, might have caused sampling errors or inaccuracies. All the patients were in sinus rhythm, and this could minimize the sampling errors. Finally, the heterogeneous etiology causing precapillary-PH might have led to other uncontrolled factors in the analysis. Further exploration is needed.With the progression of PH, the diastolic period variations in the RV and LV were related to IVS displacement and ventricular dysfunction. The temporal variations in the cardiac cycle may also be possible parameters, which can explain the severity of the disease and provide useful information about the pathophysiological mechanism of the ventricular dysfunction and indicate the prognosis for PH patients.


Diabetic heart disease is a major healthcare problem. Patients with diabetes show an excess of death from cardiovascular causes, twice as high as the general population and those with diabetes type 1 and longer duration of the disease present with more severe cardiovascular complications. Premature coronary artery disease and heart failure are leading causes of morbidity and reduced life expectancy. Multimodality cardiac imaging, including echocardiography, cardiac computed tomography, nuclear medicine, and cardiac magnetic resonance play crucial role in the diagnosis and management of different pathologies included in the definition of diabetic heart disease. In this review we summarise the utility of multi-modality cardiac imaging in characterising ischaemic and non-ischaemic causes of diabetic heart disease and give an overview of the current clinical practice. We also describe emerging imaging techniques enabling early detection of coronary artery inflammation and the non-invasive characterisation of the atherosclerotic plaque disease. Furthermore, we discuss the role of MRI-derived techniques in studying altered myocardial metabolism linking diabetes with the development of diabetic cardiomyopathy. Finally, we discuss recent data regarding the use of artificial intelligence applied to large imaging databases and how those efforts can be utilised in the future in screening of patients with diabetes for early signs of disease. World Health Organisation estimates that there are 422 million people living with diabetes mellitus worldwide and 1.5 million deaths are attributed to diabetes annually , cardiac magnetic resonance (CMR) and nuclear cardiology, has advanced our understanding and treatment of different pathologies included in the definition of diabetic heart disease. Non-invasive assessment of coronary artery disease, structural heart disease, arrhythmias, and heart failure, guides clinical management and leads to a significant improvement in patient outcomes. Multiple imaging modalities are used to detect the signs of diabetic heart disease and the full assessment frequently involves more than one type of scan.There has been also an increased interest in using hybrid and fusion modalities combining two imaging techniques within one scan and incorporating machine learning into the analysis of images with the goal to improve earlier detection of metabolic and structural abnormalities which could lead to an improvement in long-term clinical outcomes.Echocardiography plays an important role in the detection of subclinical dysfunction. Left ventricular dysfunction in patients with diabetes can have various presentations including predominantly systolic, diastolic, or mixed phenotypes . TherefoEchocardiography is often the first-line evaluation of cardiac structure and function given its high temporal and spatial resolution, safety, availability, and cost-effectiveness. Left ventricular volumes and ejection fraction derived from 3D echocardiography has shown accuracy and reproducibility comparable to cardiac MRI . AdvanceKey parameters assessing diastolic dysfunction and structural changes have been positively correlated with progression to clinical heart failure. Structural changes identified include larger end-systolic and end-diastolic dimension, greater left ventricular mass in the context of similar wall thickness and greater left atrial area . SeveralHence those echocardiographic features of diastolic dysfunction as well as left ventricular hypertrophy are often regarded as early signs that diabetes affected the myocardium . Age, obPatients with history of diabetes and significant coronary artery disease commonly present with heart failure reduced ejection fraction (HFrEF). Echocardiograms of those patients may detect regional wall motion abnormalities, alterations in strain and in the later stage also reduced ejection fraction. Abnormal global longitudinal strain (GLS) has been described as an early sign of developing HFrEF in patients with diabetes , 20. TheStress echocardiography has been shown to be an accurate and reliable imaging modality to diagnose coronary artery disease and predict the long-term outcome in patients with diabetes . ExercisIt has been shown previously that patients with diabetes have higher burden of plaque disease than those without diabetes  and the Advancements in the CT technology resulting in a reduction of the radiation doses increased the popularity of CT coronary angiography (CTA) in the assessment of CAD in patients with diabetes . In asymMyocardial computed tomography perfusion (CTP) imaging is an emerging CT-based method for detecting myocardial ischaemia with good accuracy  and corrFFR-CT is an alternative functional technique, which combines anatomic and physiologic information in a single non-invasive test. Patients with diabetes have a high burden of coronary artery disease and it has been shown that every sixth asymptomatic patient at the time of the diagnosis of diabetes has haemodynamically significant plaque disease as evaluated by FFR-CT  see an . FFR-CT European and American societies have recently introduced the use of CTA in patients with diabetes who present with a history of chest pain , 48. TheMapping of peri-coronary adipose tissue attenuation (PCAT) on CTA has been recently proposed as a non-invasive marker of coronary artery inflammation . Several82Rubidium, 13N-ammonia or 15O-water at rest and after vasodilator-stress enable calculation of coronary flow reserve  is widely used in patients with and without diabetes to detect haemodynamically significant coronary artery disease. It has been reported that in 20–25% of asymptomatic patients with the diagnosis of diabetes MPS detects ischaemia , 60 and  reserve . Moreove reserve . Due to The cardiac consequences of diabetes on the myocardium ensue from metabolic and functional alterations. CMR is a versatile imaging modality  able to Although cardiac magnetic resonance is mostly used to provide information about systolic function of the left ventricle, it can also characterise diastolic dysfunction and therefore can offer a holistic approach to the early detection of myocardial dysfunction associated with diabetes. Different MRI technique are currently available to evaluate diastolic function  allowing such measurements as longitudinal fractional shortening used when assessing patient presenting with heart failure preserved ejection fraction (HFpEF). Strain-encoded (SENC) , displacLate gadolinium images confirmed silent myocardial infarctions in 4.3% of asymptomatic type 1 diabetes patients  and in 1The community-based ICELAND-MI study, which showed that LGE diagnosis of unrecognised myocardial infarction was associated with a 45% increased mortality . Novel t1H MRS) (31P-MRS), which allows non-invasive assessment of relative concentration of PCr to ATP (PCr/ATP) as a sensitive index   and has 1H MRS) , 83. Notve index . Decreasve index . Such enve index . More re disease . It demoIncreased oxidative stress, altered substrate use, and insufficient myocardial perfusion have been proposed as the mechanisms underlying myocardial structural and functional changes observed in the diabetic heart disease. Patients with type 2 diabetes have higher global myocardial perfusion at rest and lower maximal myocardial blood flow during vasodilator-induced stress than control subjects . AdenosiOver the last decade we have also observed an increased interest in hybrid cardiac PET/MR imaging protocols, which have been incorporated into clinical workflows in many centres. PET is known for its role in quantification of myocardial perfusion and coronary flow reserve as well as visualisation and quantification of metabolic and inflammatory processes at the molecular level . Thus, wDM (Although asymptomatic cardiovascular disease is common in people with diabetes and is associated with adverse outcome, the role of multimodality cardiac imaging in screening remains debatable. Large randomised clinical trials testing the value of using imaging in early detection of diabetic heart disease are required to introduce such investigations into clinical practice. The success of novel therapies with proven cardiovascular benefit should motivate such investigations in future and lead to the development of clinical guidance utilising various cardiac imaging modalities in detecting early signs of heart disease in those patients. Patients with diabetes represent a heterogenous group and may require clinical assessment with several imaging modalities in the course of their disease. DM  risk scoDM . One couFrom the cost-efficiency point of view, echocardiography with strain imaging has the highest chance to be considered as a modality of choice in screening for early signs of diabetic heart disease. Echocardiography remains the most accessible imaging modality and with the use of novel parameters can phenotype various subtypes of heart failure associated with the diagnosis of diabetes. It is also the most versatile technique able to examine and quantify the degree of systolic and diastolic function, provide evidence of regional wall motion abnormalities, assess signs of left ventricular hypertrophy, detect an increased left atrial pressure, and describe the presence of rarer types of inherited and acquired cardiomyopathies.From the coronary artery point of view, calcium score remains to be a powerful tool for personalised risk assessment and decision making. Patients with diabetes and calcium score of zero have low event rate. Individuals with an increased calcium score may require further assessment with CTA and/or functional test to guide a wide range of preventive therapies and treatment strategies. In symptomatic patients, CTA has a well-established role and the addition of computational fraction flow reserve as well as novel imaging markers such as PCAT may strengthen its role even further. Given the complexity of mechanisms leading to myocardial involvement in patients with diabetes and all strengths and weaknesses of each imaging modality, the role of imaging in screening of asymptomatic patients with diabetes remains questionable.13C magnetic resonance spectroscopy allow assessment of altered myocardial metabolism in the diabetic heart and holds a promise to uncover the link between diabetes and heart diseases. Noteworthy, MRI provides multiple metrics assessing multi-organ health within one acquisition, which is particularly valuable in case of a systemic disease such as diabetes.The core value of cardiac magnetic resonance lies in the tissue characterisation, the detection of diffuse myocardial fibrosis, and an increase myocardial triglyceride accumulation. MR spectroscopy techniques including novel hyperpolarised Another way of utilising multi-modality imaging techniques within clinical screening pathways is to focus on the highest risk of certain outcome and choose a test, which is most likely to identify that outcome. For example, in patients with diabetes who are at high risk of developing coronary artery disease, CTA will identify patients with obstructive coronary artery disease or left main stem disease. Depending on local availability, stress echocardiography and perfusion scintigraphy or perfusion CMR could also be considered as first line tests to detect haemodynamically significant coronary artery disease. On the other hand, in those patients who have higher risk of heart failure, ECG and echocardiography will be used as the first line investigations followed by CMR. The growing interest in the use of artificial intelligence in the field of imaging will certainly produce new insights into such complex pathophysiology. The rapid increase in the number of studies confirming superiority of AI algorithms in analysing imaging data is very encouraging. Most importantly, AI will also increase standardisation of interpretation and quantification in imaging. The role of AI has been also confirmed in deep phenotyping of highly heterogenous cohort of patients with diabetes, which on its own could personalise the choice of most appropriate imaging modality in various cohorts of patients. The myriad of applications of AI is a harbinger of a potential breakthrough in how we will come to view the utility of various imaging markers in the early detection of diabetic heart disease is the not-so-distant future.MW wrote the first draft of the manuscript and finalised the last version after co-authors comments. MG prepared


In ST-segment elevation myocardial infarction (STEMI), predictors of subclinical dysfunction of remote myocardium are unknown. We prospectively aimed at identifying clinical and biochemical correlates of remote subclinical dysfunction and its impact on left ventricular ejection fraction (LVEF).p = 0.19) STEMI underwent echocardiography at 5 ± 2 days after onset and at 8 ± 2-month follow-up, and were compared to 13 age and sex-matched (63.3 ± 11.4) healthy controls. All 16 left ventricular (LV) segments were grouped into ischemic, border, and remote myocardium: mean value of longitudinal strain (LS) within grouped segments were expressed as iLS, bLS, rLS, respectively. LV end-diastolic (EDV), end-systolic (ESV) volumes indexed for body surface area , LVEF and global LS (GLS) were determined. Creatinine, glomerular filtration rate, admission level of NT-pro-brain-natriuretic peptide (NT-proBNP) and troponin peaks were considered for the analysis.One-hundred thirty-three patients  with first successfully treated , but lower than that in controls  and similar to bLS , and did not differ between patients with single or multivessel coronary artery disease (CAD). At multivariate regression analysis, only admission NT-proBNP levels but not peak Tn levels independently predicted rLS , as well as iLS . Both at baseline and at follow-up, rLS correlated to LVEF similarly to iLS and bLS . Median value of rLS at baseline was 15%: compared to patients with rLS ≥ 15% at baseline, patients with rLS < 15% showed lower LVEF  and GLS (16.3 ± 3.9 vs. 19.9 ± 3.2), and higher EDVi  and ESVi  at follow-up.At baseline, rLS (15.5 ± 4.4) was better than iLS  is predicted by elevated NT-proBNP; (2) could be independent of CAD extent and infarct size; (3) is associated to worse LV morphological and functional indexes at follow-up. ST-Segment Elevation Myocardial Infarction (STEMI) is the most acute manifestation of coronary artery disease (CAD). Although current therapies have significantly decreased death for STEMI in the past 3 decades , long-teCharacterization of myocardium inside and outside infarcted area can be made only by using sophisticated imaging tools, since assessment of LV ejection fraction (LVEF) or wall motion abnormalities is poorly sensitive in catching subtle functional changes within viable myocardium . Based oBiochemical predictors of subtle contractile dysfunction of remote myocardium, as well as its functional impact in comparison with infarct and borderline myocardium, have not been investigated before in large cohorts of STEMI patients. In this prospective single center study, we aimed at: (1) detecting predictors of LS in remote myocardium, as compared to infarct and borderline myocardium, by echocardiographic LS, during the sub-acute phase of first successfully treated STEMI; (2) verifying its impact on LVEF; (3) assessing echocardiographic data at 6-month follow-up, stratified by value of baseline LS in remote myocardium.A consecutive series of patients admitted to our Intensive Cardiac Care Unit for a first STEMI, from February 2018 to May 2021, was screened. The diagnosis of STEMI was based on the presence of typical chest pain or equivalents, lasting at least 20 min, associated with the persistence of the ST-segment elevation  and elevation of cardiac troponin (Tn) and creatine-kinase MB fraction (CK-MB) with at least a value above the 99th percentile of the upper reference limit . PatientBlood samples for the dosage of high sensitivity Tn, NT-pro-brain-natriuretic peptide (NT-proBNP) and creatinine serum levels were obtained upon arrival of the patient in the emergency room. Subsequently, dosage of Tn was repeated after PCI, at 6 and 12 h and then daily until normalization of values or discharge. Although it is weak to assess the infarct size, peak values of Tn was considered for the analysis, while value of NT-proBNP and creatinine at admission were taken into account, in order to avoid effect of treatment on serum level of biomarkers.Transthoracic echocardiography was performed by using last generation ultrasound machines  equipped with a two-dimensional X3 probe, both at baseline  and at 6-month follow-up. LV end-diastolic (EDV) and end-systolic (ESV) volumes were obtained from 4- and 2-chamber apical views using the modified Simpson’s biplane method, and were indexed for body surface area . LVEF was calculated as [(EDV-ESV)/EDV] × 100.For regional contractile function assessment, a 16-segment myocardial model was used, according to the recommendations of the American Heart Association . All myoAnalysis of LS was automatically performed off-line, by tracing endocardial border in apical 4, 3, and 2-chamber views, using Autostrain package software . Global LS (GLS) was obtained as mean value of the three views and LS values in each myocardial segment were considered. The mean value of LS within ischemic, border, and remote zones was taken into account for the analysis and expressed as iLS, bLS, and rLS, respectively. GLS, iLS, bLS, and rLS were reported as absolute values. Patients with suboptimal images were excluded from the analysis.t-test or one-way ANOVA for continuous variables or by Chi-square test for categorical variables. Multiple comparisons were corrected by Bonferroni method. Correlations were tested by Pearson test and compared by z-statistics. Univariate and multivariate linear regression analyses were performed: predictors with p ≤ 0.10 at univariate analysis entered multivariate analysis, which was adjusted for age, hypertension, diabetes, dyslipidemia, smoking, and presence of pre-infarctual angina. Within-group differences between baseline and follow-up were analyzed by two-way ANOVA for repeated measures. Finally, all patients were stratified into 2 groups, basing on median value of rLS at baseline: differences between the two groups in clinical, biological and echocardiographic data were assessed both at baseline and at follow-up. A p-value < 0.05 was considered as statistical significance for all analyses.Statistical analysis was performed using SPSS 21.0 statistical software . After checking for normality distribution by Kolmogorov-Smirnov test, continuous variables were expressed as mean ± standard deviation (SD) if parametric and as logarithmic transformation if non-parametric. Categorical variables were expressed as percentage. Differences were assessed by Student n = 77, 58%) had single-vessel CAD, while 42 (32%) had two-vessel and 14 (10%) three-vessel CAD . Seventy-two (54%) patients presented with anterior STEMI, while 61 (46%) patients with non-anterior STEMI (p = 0.19).Out of 180 patients enrolled at baseline, 47 patients were subsequently excluded . Thus, 1p < 0.001), with rLS being higher than iLS (p < 0.001), but similar to bLS (p = 0.99) and lower than controls (p < 0.001). ILS also differed from bLS (p = 0.003)  .p = 0.66), neither iLS (p = 0.76), or bLS (p = 0.22) differed between patients with single-vessel and multi-vessel CAD .Multi-vessel CAD did not affect LS more than single-vessel CAD: nor rLS (ssel CAD . Similarp = 0.001), whereas iLS was predicted by NT-proBNP  and creatinine values , and bLS by non-anterior location of STEMI .Univariate and multivariate analyses were performed separately for rLS, iLS, and bLS. Results of univariate analysis are reported in z-Test −0.166, p = 0.43 for comparison of correlation coefficients)  .n = 67) and group 2 . Patients with baseline rLS < 15% more frequently had anterior STEMI and lower renal function, whereas showed only a trend to greater infarct size than patients with baseline rLS ≥ 15% , as well as rLS , iLS , and bLS , while changes of EDVi (54.9 ± 26.4 vs. 51.3 ± 12.5 at baseline) and of ESVi (24.1 ± 14.2 vs. 26.3 ± 10.2 at baseline) were not significant . At follow-up, rLS still correlated with LVEF similarly to iLS and bLS   .Interestingly, patients with baseline rLS < 15% showed greater improvement of regional and global LV contractility than patients with baseline rLS ≥ 15%, at the expense of greater increase of EDVi . HoweverIn a consecutive series of patients with first optimally treated STEMI and prospectively followed-up by echocardiography, we found that: (1) in the sub-acute phase of STEMI iLS, rLS, and bLS are independent of extent of CAD and are associated to LVEF; (2) NT-proBNP level at admission is an independent predictor of rLS; (3) despite an overall improvement of contractile function over time, patients with more impaired rLS at baseline show worse LV morphological and functional indexes also at follow-up. To the best of our knowledge, this is the first study attempting to characterize remote myocardium after ischemic injury by biochemical and imaging approach: our results suggest that impaired remote myocardial function as assessed by LS is associated to a worse LVEF at follow up which may eventually lead to heart failure (HF).Our data about contractile dysfunction of remote myocardium in STEMI patients expand previous findings , 13, 14,Anterior STEMI particularly impairs rLS : indeed,LV strain predicts prognosis after AMI , 37: parIn conclusion, for long time every effort in the setting of STEMI was made in the attempt to reduce the ischemic wavefront, as infarct size was considered one of the main determinants of adverse LV remodeling and outcome. Basing on our findings, however, patients with STEMI and high level of NT-proBNP since admission may have impairment of contractile function spreading beyond infarct area, regardless of CAD extent. Contribution of remote myocardium to global LV contractile function would explain why patients with similar extent of infarct area have different LVEF evolutions. If confirmed in further large cohorts of STEMI patients, the present findings may open the road toward treatments in the acute and sub-acute phase of STEMI, aiming not only to limit the ischemic wavefront, but also to preserve structural and functional integrity of myocardium surrounding necrosis, by decreasing the maladaptive response to the ischemic injury. Even patients with limited infarct size may need a careful follow-up in order to timely detect and prevent adverse remodeling. Future studies should be encouraged in order to test efficacy of a more aggressive pharmacological treatment, employing advanced HF therapy since the sub-acute phase of STEMI.The most important limitation of our study is the lack of imaging data deriving from a tool able to precisely delineate infarct area, such as late gadolinium enhancement CMR. Current results should be confirmed with appropriate advanced myocardial imaging technique that are not available in the present study. However, although less precise than late gadolinium enhancement quantification, Tn peak has been previously validated as surrogate of infarct size . DiffereThe original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.GD collected the data and designed the analysis. GLo designed the analysis, performed the analysis, and wrote the manuscript. LM collected the data. FG, AL, DP, GLi, MM, and GAL reviewed the manuscript. FC reviewed and approved the manuscript. All authors contributed to the article and approved the submitted version.


Radiation therapy (RT) plays an integral role in treating thoracic cancers, despite the risk of radiation-induced cardiotoxicity. We hypothesize that our newly developed magnetic resonance imaging (MRI)-based contractility index (ContractiX) is a sensitive marker for early detection of RT-induced cardiotoxicity in a preclinical rat model of thoracic cancer RT. Adult salt-sensitive rats received image-guided heart RT and were imaged with MRI at 8 weeks and 10 weeks post-RT or sham. The MRI exam included cine and tagging sequences to measure left-ventricular ejection fraction (LVEF), mass, myocardial strain, and ContractiX. Furthermore, ventricular torsion, diastolic strain rate, and mechanical dyssynchrony were measured. Statistical analyses were performed between the sham, 8 weeks post-RT, and 10 weeks post-RT MRI parameters. The results showed that both LVEF and myocardial mass increased post-RT. Peak systolic strain and ContractiX significantly decreased post-RT, with a more relative reduction in ContractiX compared to strain. ContractiX showed an inverse nonlinear relationship with LVEF and continuously decreased with time post-RT. While early diastolic strain rate and mechanical dyssynchrony significantly changed post-RT, ventricular torsion changes were not significant post-RT. In conclusion, ContractiX measured via non-contrast MRI is a sensitive early marker for the detection of subclinical cardiac dysfunction post-RT, and it is superior to other MRI cardiac measures. Along with systemic therapies, radiation therapy (RT) plays an integral role in treating advanced lung cancer. However, the incidence of RT-induced cardiac complications in this patient population is as high as 33% ,2,3. RecThe current paradigm for cardiac function assessment and management of cardiovascular disease relies primarily upon the assessment of global cardiac function, e.g., left ventricle ejection fraction (LVEF) ,13. HoweMagnetic resonance imaging (MRI) tagging  allows fIn this study, we investigated the capability of advanced MRI-generated parameters of heart mechanics for characterizing the myocardial contractility patterns post-RT and for early detection of RT-induced cardiotoxicity in a pre-clinical rat model of radiation-induced cardiotoxicity. We present the contractility index (ContractiX) derived from regional strain parameters. We hypothesize that ContractiX is a sensitive marker for early detection of RT-induced cardiotoxicity. We also examined the effect of RT on other MRI-generated heart contractility parameters, including ventricular torsion, diastolic strain rate, and mechanical dyssynchrony.This study was approved by the Medical College of Wisconsin Institutional Animal and Use Care Committee. Adult female Dahl salt-sensitive (SS) rats, aged ~10 weeks, were randomized into two groups: sham-treated (N = 7), that were imaged at 8 weeks post-sham, and RT-treated (N = 5) that were imaged at both 8 weeks and 10 weeks post-RT, as previously described . The RT × 176, the field of view (FOV) = 40 mm × 40 mm, slice thickness = 1 mm, acquisition bandwidth = 526 Hz/pixel, #averages = 2, #cardiac phases = 20, scan time ~2 min/slice. The tagging sequence imaging parameters were similar to cine imaging, except for the following: matrix = 256 × 256, acquisition bandwidth = 375 Hz/pixel, #averages = 3, scan time = 4–5 min/slice.The rats were imaged on a small-animal 9.4T MRI scanner with a 30-cm bore diameter  using a 4-element surface coil . The MRIThe cine images were analyzed using the cvi42  software to measure left ventricle (LV) end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), EF, and mass. The tagged images were analyzed using the SinMod  techniquThe ContractiX parameter is introduced as a new measure of heart contractility performance derived from regional strain measurements in different segments in the LV AHA segmental model. First, the strain value for each rat was calculated as the mean of peak systolic strain from all segments. ContractiX was generated as the percentage of normally contracting myocardium for each rat, which was calculated as the number of normally contracting segments, divided by the total number of segments, and multiplied by 100; therefore, ContractiX ranges from 0  to 100 . A myocardial segment was considered normally contracting if its peak systolic strain exceeded a threshold value, calculated as the mean minus one standard deviation (SD) of the strain values from all sham rats. ContractiX values were calculated from different strain components , longitudinal (ContractiX-long), and radial (ContractiX-rad)) and changes in ContractiX post-RT were compared to those in LVEF and strain values. ContractiX was also calculated from strains in more than one direction, starting with circumferential and longitudinal directions (ContractiX-CL) and then all three directions (ContractiX-CLR).Ventricular torsion, another parameter of systolic function, was measured as the difference between basal and apical rotation angles at peak systole divided by the distance between the basal and apical slices. Besides systolic function, early-diastolic strain rate (SR) was calculated in different directions , SR-rr , SR-ll ). For presentation clarity, diastolic SR measures are represented in absolute values. Finally, to assess myocardial mechanical dyssynchrony, the standard deviations of time-to-peak (TTP) systolic strain between different myocardial segments, based on the AHA 17-segment model, were calculated in different directions .p < 0.05 was considered significant. Bland-Altman analysis [All measurements were represented as mean ± standard deviation (SD). ANOVA analysis with the Tukey post hoc test was conducted for multiple comparisons between different rat groups. Spearman correlation analysis was conducted between ContractiX and LVEF. analysis  was condAs shown in The ContractiX parameter significantly reduced post-RT in all directions, as shown in p < 0.01) and 30 ± 6.9% (p < 0.01) at 8-weeks and 10-weeks post-RT, respectively, where the degree of reduction post-RT lied between those of ContractiX-circ and ContractiX-long. When calculating ContractiX using all strain components , ContractiX-CLR decreased from 55 ± 17.6% in the sham rats to 37 ± 6.7% (p = 0.03) and 25 ± 4.8% (p < 0.01) at 8-weeks and 10-weeks post-RT, respectively.While normal LVEF was maintained post-RT, all ContractiX parameters showed a continuous decrease post-RT. This can be explained by the nonlinear inverse relationship between LVEF and ContractiX , in whicBesides strain, other heart contractility parameters also demonstrated worsening cardiac function post-RT . VentricIn this study, we investigated the effect of localized heart irradiation on myocardial contractility patterns by studying different MRI-generated parameters that measure different aspects of systolic and diastolic functions, as well as mechanical dyssynchrony. The results demonstrated the sensitivity of the newly developed parameter, ContractiX, for early detection of subclinical cardiac dysfunction post-RT despite normal LVEF.The results from this study illustrate the multifaceted effect of RT on myocardial contractility. Many reports, both clinically and pre-clinically, measure RT-induced cardiotoxicity utilizing LVEF as a measure of cardiac function ,32,33,34Our results demonstrate the value of ContractiX as an early marker of subclinical cardiac dysfunction post-RT despite normal global function . While nThere are three unique features of the introduced ContractiX parameter: (1) it can be calculated based on different strain components or combinations of these strain values; (2) it is agnostic to the strain acquisition sequence and analysis technique; and (3) the threshold values are determined utilizing the mean and standard deviations of strain measurements from normal subjects in the population being investigated for accurate differentiation between normal and pathological cases. The last feature is important as normal strain ranges could be different in different studied groups, species or even based on the strain acquisition and analysis techniques.Our results also demonstrate the effect of RT on other parameters of heart mechanics. For example, ventricular torsion showed a small, non-significant decrease post-RT. While this parameter did not distinguish early changes post-RT well in this study, it may be useful to compare individuals in other situations, e.g., with different doses or time points post-RT. The study showed that RT affects not only systolic function but also diastolic function ,33. ThisOur study has some limitations. The first limitation is the small number of animals used in the study. The main purpose of this study was to introduce the new measure, ContractiX, and provide a proof-of-concept about its sensitivity for detecting subclinical cardiac dysfunction, which was demonstrated by the results despite the small number of animals. However, future studies on a larger cohort are warranted to confirm these results with sufficient statistical power.Another limitation of our study is that we did not include another group of salt-resistant rats. The choice of salt-sensitive rats for this study was based on their cardiovascular profile, which is more vulnerable to cardiac injuries ,26,36 (rAnother limitation of the current study is the unavailability of perfusion or late gadolinium enhancement (LGE) MRI data. However, the focus of this study was to characterize the cardiac function and myocardial contractility patterns shortly after RT and before global heart function is affected, where ischemia development and myocardial infarction are not expected to occur during the acute phase post-RT. Nevertheless, larger studies with longer follow-up times are warranted to confirm the results from this study and evaluate late RT effects on the heart. Although the focus of this study was on situations where the heart receives large radiation doses based on the tumor’s proximity to the heart , the presented imaging biomarkers may be valuable in other cancer types that incur incidental heart irradiation, e.g., in breast cancer or lymphoma, and they should be evaluated in these types of exposures in the future.There is great potential for the translational value of this study, especially in cases of significant radiation to the heart when the tumor’s location is close to the heart ,37. The Finally, it should be noted that cardiac MRI provides a plethora of techniques for the comprehensive evaluation of heart health, including assessment of systolic function, diastolic function, hemodynamics, and tissue characterization . AlthougThe results from this study characterize the effect of RT on myocardial contractility patterns and demonstrate the value of the newly defined ContractiX parameter as a sensitive early marker of subclinical cardiac dysfunction post-RT, that might be superior to other measures of cardiac function, such as LVEF and strain, if proved by further studies.


Prominent trabecular left ventricular (LV) meshwork and deep intertrabecular LV recesses are featuring LV non-compaction (LVNC). The aim of this study was to evaluate tricuspid annular (TA) morphological and functional abnormalities by three-dimensional speckle-tracking echocardiography (3DSTE) in patients with LVNC without right ventricular (RV) involvement.This study consisted of 21 patients with isolated LVNC, from which 6 cases were excluded due to inferior image quality. The remaining patient group consisted of 15 subjects with a mean age of 52.1 ± 11.4 years . LVNC was defined according to the Jenni's criteria. Their results were compared to 21 age- and gender-matched healthy controls . Complete routine 2-dimensional Doppler echocardiographic examination was performed in all the patients with isolated LVNC and healthy controls. End-systolic and end-diastolic TA dimensions were assessed on selected planes derived from full-volume 3D echocardiographic datasets during 3DSTE.Patients with isolated LVNC showed significantly dilated end-systolic and end-diastolic TA diameter and area, which were accompanied with preserved TA functional properties and associated with right atrial (RA) volumes. TA plane systolic excursion (TAPSE) showed mild correlations with TA fractional area change (TAFAC) and TA fractional shortening (TAFS). No correlations could be demonstrated between TAPSE and TA morphological features. Extent of LVNC did not correlate with any echocardiographic parameters.TA is dilated with preserved sphincter-like function in patients with isolated LVNC. Longitudinal (TAPSE) and sphincter-like (TAFAC and TAFS) TA movements correlate with each other. TA dilation is associated with an increased RA volumes respecting cardiac cycle. Left ventricular (LV) non-compaction (LVNC) is a rare cardiomyopathy due to arrest of the normal maturation process of the myocardium –3. It isThe tricuspid valve (TV) is a complex anatomical structure, which incorporates the three-dimensional (3D) saddle-shaped annulus fibrosus [tricuspid annulus (TA)] . 3D specThis study comprised patients with isolated LVNC, which was defined according to the Jenni's criteria  5)::5):- An excessively thickened LV myocardial wall with a 2-layered structure comprising a compacted layer on the epicardial side and a non-compacted layer of prominent trabeculations and deep intertrabecular recesses on the endocardial side.- A non-compacted/compacted LV myocardium thickness ratio > 2 measured at the moment of maximal thickness in end-systole.- Color Doppler evidence of deep intertrabecular recesses in communication with the LV cavity.- Absence of coexisting cardiac anomalies.Motion Analysis of the heart and Great vessels bY three-dimensionAl speckle-tRacking echocardiography in Pathological cases (MAGYAR-Path) Study, which aimed to examine valvular annular abnormalities in different disorders among other aims (“Magyar” means “Hungarian” in hungarian language). This methodology complied with the Declaration of Helsinki, informed consent was obtained from all the patients and healthy controls, and the institutional review board approved it (registration number: 71/2011).Their results were compared to age- and gender-matched healthy controls who were considered to be healthy in the absence of any disorder, other pathological state or risk factor, regular drug use, and negative electrocardiographic and echocardiographic findings. Complete routine 2-dimensional (2D) Doppler echocardiographic examination was performed in all the patients with isolated LVNC and healthy controls. This study is a part of the TM echocardiographic machine  attached to a PST-30SBP (1–5 MHz) phased-array transducer was used   and righwas used .TM echocardiographic machine  with a 1–4 MHz matrix phased-array PST-25SX transducer was used. Data acquisitions were performed within a single breath-hold and during a constant RR interval. In all the cases, 6 wedge-shaped subvolumes were acquired and then the software created a full volumes pyramid-shaped 3D dataset, where the analysis and chamber quantification were done later  . Shortly- Tricuspid annular diameter (TAD), defined as the perpendicular line drawn from the peak of TA curvature to the middle of the straight TA border.- Tricuspid annular area (TAA), measured by planimetry.- Tricuspid annular perimeter (TAP), measured by planimetry.- Tricuspid annular fractional shortening (TAFS) = [(end-diastolic TAD - end-systolic TAD)/end-diastolic TAD] × 100.- Tricuspid annular fractional area change (TAFAC) = [(end-diastolic TAA - end-systolic TAA)/end-diastolic TAA] × 100.The same software was used for virtual 3D model creation and quantification of the right atrium (RA) . First, t-test was used, while if it was found non-normally distributed, the Mann–Whitney U test or the Wilcoxon signed-rank test was performed. The chi-squared test/Fisher's exact test was used for statistical analysis as appropriate. Correlations were established by calculation of Pearson's correlation coefficients. They were used for intraobserver and interobserver correlations as well. Intraobserver and interobserver agreements were evaluated using the Bland–Altman method. All the tests were two-sided. p < 0.05 was defined as statistical significant. The statistical package used was SPSS software version 25.1.Calculated data were demonstrated as mean ± SD or absolute numbers/percentages as appropriate. Homogeneity of variances were assessed by Levene's test. If a dataset proved to be normally distributed, the Student's 2, respectively. Clinical data of patients with isolated LVNC and healthy controls are given in This study consisted of 21 patients with isolated LVNC, from which 6 cases were excluded due to inferior image quality. The remaining patient group consisted of 15 subjects with a mean age of 52.1 ± 11.4 years . Although RV is more trabeculated in normal circumstances than the LV, none of the cases showed obvious RV hypertrabeculation and typical signs of NC. The control group consisted of 21 age- and gender-matched healthy subjects . Body surface area of healthy controls and patients with isolated LVNC proved to be 1.82 ± 0.23 and 1.82 ± 0.34 m2 and 9.8 ± 2.3 cm2/m2 in patients with isolated LVNC, respectively. The mean number of non-compacted segments proved to be 6.9 ± 2.0. Grade 1 and 2 mitral regurgitation (MR) could be demonstratred in 5 and 5 patients with isolated LVNC, respectively. Higher grade of MR could not be found. Grade 1 and 2 tricuspid regurgitation (TR) could be demonstrated in 4 and 1 patients with isolated LVNC, respectively. Only one isolated patient with LVNC showed grade 4 TR. None of patients with isolated LVNC and healthy controls showed significant valvular stenosis. TAPSE and RVFAC proved to be 13.9 ± 3.9 mm and 34.1 ± 2.7%, respectively, in patients with isolated LVNC.Standard 2D echocardiographic data are shown in Patients with isolated LVNC showed significantly dilated end-systolic and end-diastolic TA diameter and area, which were accompanied with preserved TA functional properties. RA volumes respecting cardiac cycle proved to be dilated in patients with isolated LVNC .r = 0.39, p = 0.05; r = 0.36, p = 0.05, respectively) and TAFS . No correlations could be demonstrated between TAPSE and RVFAC and TA morphological parameters. RA strains did not correlate with any TA morphological and functional features. Extent of LVNC did not correlate with any echocardiographic parameters. End-diastolic and end-systolic TAD and TAA correlated with all the RA volumes, while end-diastolic and end-systolic TAP showed correlations with Vmin only. Only TAFS correlated with Vmin, other correlations between TA functional properties, and RA volumes could not be detected  and 9 out of 30 healthy subjects (30%) were excluded due to insufficient image quality . The overall feasibility of measurements proved to be 70%.Tricuspid annulus has a complex, asymmetrical, and saddle-shaped ellipsoid structure with a dynamic nature respecting cardiac cycle. Several echocardiographic methods can be used for morphological and functional assessment of the TA including simple M-mode echocardiography-derived TAPSE, which featuring its systolic longitudinal movement along long-axis of the RV . TAPSE iIsolated LVNC was found to be associated with significant abnormalities in myocardial mechanics in several studies. Systolic LV dysfunction did not confine to the non-compacted segments in isolated LVNC, non-compacted and compacted LV segments have been demonstrated to have comparably increased regional LV volumes, reduced regional LV ejection fractions, and decreased LV strains demonstrating deteriorated LV function , 16. LV According to these abnormalities accompanied with LVNC, there can be a question, what happens with the right heart in isolated form of LVNC. In a recent study, increased RA volumes respecting heart cycle could be demonstrated . In contThere are little information on the tricuspid valve in LVNC and most of them are case reports focusing on associated TV abnormalities , 24. In Image quality of 3DSTE is lower than that of 2D echocardiography, which could affect measurements –10.Only clear patients with LVNC were evaluated and biventricular form of NC or unclear cases with extensive RV hypertrabecularization was excluded from this study.Only a limited number of patients with LVNC were assessed. However, it could be considered that LVNC is a rare disease and results origin from a single center .Some patients with LVNC showed small grade of TA regurgitation. Moreover, from risk factors, hypertension and hypercholesterolemia were relatively frequent in the group of patients with isolated LVNC, which could affect results.The normal ranges of 3DSTE-derived TA parameters are missing from the literature; therefore, comparison of TA parameters of healthy control subjects to these data is not possible at this moment.End-systolic and end-diastolic TA dimensions were given for all the controls and patients with isolated LVNC. Other parameter of TA was not aimed to be measured during evaluations.Comparison results of patients with LVNC with that of a control population of patients with dilated cardiomyopathy (DCM) without LVNC would have improved understanding the findings. However, involvement of patients with DCM was not possible at the time of echocardiographic examinations.Tricuspid regurgitation was quantified by visual assessment. More advanced TR quantification system was not applied in this study.Tricuspid annulus is dilated with preserved sphincter-like function in patients with isolated LVNC. Longitudinal (TAPSE) and sphincter-like (TAFAC and TAFS) TA movements correlate with each other. TA dilation is associated with an increased RA volumes respecting cardiac cycle.The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by Institutional Review Board at the University of Szeged (Registration Number: 71/2011). The patients/participants provided their written informed consent to participate in this study.AN: hypothesis and writing paper. ÁK: performing 3DSTE, measurements, and statistics. GR: performing measurements and statistics. All authors contributed to the article and approved the submitted version.This work was supported by University of Szeged Open Access Fund.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.


Percutaneous interventions have completely refashioned the management of children with congenital heart diseases (CHD) and the use of non-invasive imaging has become the gold standard to plan and guide these procedures in the modern era. We are now facing a dual challenge to improve the standard of care in low-risk patients, and to shift our strategies from the classic open chest surgery to imaging-guided percutaneous interventions in high-risk patients. Such rapid evolution of ultrasound technologies over the last 20 years have permitted the integration of transthoracic, transesophageal and intracardiac echocardiography into the interventional workflow to improve image guidance and reduce radiation burden from fluoroscopy and angiography. Specifically, miniaturization of transesophageal probe and advances in three-dimensional (3D) imaging techniques have enabled real-time 3D image guidance during complex interventional procedure, In addition, multimodality and fusion imaging techniques harness the strengths of different modalities to enhance understanding of anatomical and spatial relationship between different structures, improving communication and coordination between interventionalists and imaging specialists. In this review, we aim to provide an overview of 3D imaging modalities and multimodal fusion in procedural planning and live guidance of percutaneous interventions. At the present times, 3D imaging can no longer be considered a luxury but a routine clinical tool to improve procedural success and patient outcomes. Percutaneous interventions have completely refashioned the management of children with congenital heart diseases (CHD) and the use of non-invasive imaging has become the gold standard to plan and guide these procedures in the modern era.Transesophageal probe miniaturization and advanced live Three-dimensional (3D) imaging have permitted a massive step forward in the ultrasound imaging guidance, and 3D echocardiography is now recommended to guide catheter-based interventions , since iIn addition, fusion imaging systems, anatomical intelligence and multimodality imaging can improve the understanding of anatomical and spatial relationship between different structures and provide better communication and coordination between interventionalists and imaging specialists.In this review, we aim to provide a “state of the art” of the different imaging technologies that have been integrated to the catheterization laboratory workflow and that are going to shape the future of congenital transcatheter procedures.Transthoracic echocardiography is the milestone of imaging in CHDs and should be performed before and after any cardiac catheterization procedure. In the pre-procedural planning it guarantees a complete anatomical assessment; it can be helpful in refining the diagnosis in patients referred for percutaneous procedures, and in determining the need for mechanical support in presence of ventricular dysfunction . In the Although the role of TTE has been limited in the catheterization laboratory in favor of transesophageal and intracardiac echocardiography in older patients, it still plays a key role in some procedures, such as patent ductus arteriosus closure in premature babies , atrial Transesophageal echocardiography is considered the gold standard technique to guide interventional procedures. Miniaturization of probes allows the utilization in neonates, with a suggested weight-limit of > 3.0–3.5 kg for the mini-multiplane probe and > 2.5 kg for the micro-multiplane one . Adult pTransesophageal Echocardiography (TEE) image quality is better than TTE when analyzing atrial and ventricular defects, left sided lesions and to monitor the catheter position , due to Transesophageal Echocardiography (TEE) decreases fluoroscopic time, radiation  and contFor patient comfort, TEE in the catheterization laboratory is usually performed under sedation/general anesthesia, thus requiring orotracheal intubation. Probe insertion requires expertise to avoid esophageal injuries. Imagers should also be familiar with some technical features of probes, such as the critical tip temperature above which probes are shutdown to prevent esophageal burns  .Echocardiography is nowadays such a multimodality tool that imagers can easily pass from bidimensional echocardiography (2D) standard images to 3D detailed anatomy of cardiac structures and multiplane reconstruction.3DE adds value to 2D technique, since it allows a real 3D visualization of complex cardiac anatomies that is, in 2DE, only in imagers’ mind. However, it should be remembered that the acquisition of good 2D images is fundamental to obtain valuable 3D data. Thus, 2D and 3D echocardiography  have a complementary role during interventional procedures, and it is recommended to include 2D, Color flow and spectral Doppler imaging as part of baseline TEE assessment .Currently available 3D TEE transducers operating frequencies ranges between 5 and 7 MHZ. There are different 3D acquisition modes that can be used during procedures guidance, including , 12:-2D simultaneous multiplane: it gathers 360° images, so more than one plane of visualization is available simultaneously (X-plane), with the main disadvantage of a low temporary resolution.-Real-time 3D (live 3D and 3D zoom): it allows an adjustable pyramidal volume acquisition (around 30° × 60°). It requires a small region of interest to preserve a satisfactory spatial and temporal resolution (frame rate: 20–30 HZ) . It is t-ECG-gated multi-beat: the acquisition of a large field of view  with high-temporal resolution (frame rate: > 30 HZ) makes this modality widely used in pediatric interventions. The drawback related to the potential creation of breathing artifacts (stitching artifacts), can be easily resolved during interventional echocardiography by briefly suspending mechanical ventilation.-3DE color flow Doppler: it is an additional tool to the above modalities, but its use reduces temporary resolution.Phased-array intracardiac Echocardiography (ICE) requires an additional venous femoral approach (8 or 10 F) to advance the ICE catheter to the right atrium and displays cardiac images from inside the heart. The transducer can be deflected in four directions and is available with 2D and Color-Doppler techniques, but imaging is limited to a single longitudinal plane (90°) . It prov3D technology is also available, with the possibility of acquiring a volume of 60° × 15° at a volume rate of 20, on a 10-French probe , 17. HowIntracardiac Echocardiography (ICE) can be performed by the interventionalists themselves, usually under local anesthesia, thus avoiding intubation and the risks related to esophageal trauma. It also reduces fluoroscopy exposure and procedural timing . HoweverTo provide an efficient procedure and the best as possible result, a good communication and coordination between interventionalists and imaging specialists is mandatory, starting from pre-procedural planning to post-procedural monitoring. During the procedures, they should use a common terminology and spatial orientation. The echocardiographer must be familiar with procedures and guarantee the best echocardiographic projections to help the interventionalists who, in turns, should communicate effectively with the imagers and pay attention to his suggestions .These considerations lead to an important message: in the Cath Lab, physicians cannot improvise as imagers. As consequence, a dedicated and standardized training in large-volume centers (> 500 TEE/year) under the guidance of senior experts, and including a defined number of different procedures as well as the possibilities of obtaining international certifications is advocated and should be followed by cardiologists who will be in charge of guiding percutaneous procedures, as recommended by scientific societies . This isPercutaneous technique is now considered the treatment of choice for OS-ASD closure . TTE is -number, size, and area of defects: for a single defect, the largest diameter measured in two perpendicular planes is taken for sizing. Defects > 38 mm are considered as complex, but percutaneous closure has been reported in highly expertise centers .-rims’ size: for a complete 2D evaluation, a rotation from 0° to 180° should be performed; rims are measured at approximately 0° (posterior and antero-inferior), 45° (posterior-inferior and antero-superior), 90° (posterior-inferior and posterior-superior), 135°(coronary-sinus and posterior-superior) ; to date-features of the interatrial septum, particularly the presence of atrial septal aneurysm and/or multifenestrated septum .-pulmonary venous returns.3DE should routinely be used in ASD assessment, and some live 3D modalities can rapidly be acquired during procedures.en face views of defects, either from the right or from the left atrium, and a more precise localization and definition of the surrounding structures, intuitive for interventionalists  is nowadays a valid alternative to surgical closure .Imagers should know the main steps of the procedure, which could be performed with either an anterograde or retrograde approach.Transthoracic Echocardiography (TTE) and TEE, either 2D or 3D, are mandatory in the preoperative and intraoperative phase respectively, to determinate the VSD location, morphology, size, the relationship to the aorta (for pmVSD) and to make the device selection choice.en face view of VSDs from the right or left ventricular side and a complete evaluation of relative changes in VSD area throughout the cardiac cycle, with an overall acquisition time close to that of a 2DE study  dataset is helpful in targeting the optimal puncture site, and intraoprocedural TEE or ICE are mandatory to guide the puncture and prevent complications , 47.Patients with CHDs are at risk for surgical reoperations and carry a high surgical risk, often due to previous multiple interventions. So, the interest in percutaneous valve-in-valve implantations is growing, especially in patients with Ebstein anomaly with failing bioprosthesis  and in aSevere systemic tricuspid valve regurgitation (STVR) is common either after atrial switch operations or in patients with congenitally corrected transposition of great arteries, and percutaneous repair with MitraClip devices might represent an option to improve symptoms in these complex patients , 53. To The goal of percutaneous balloon aortic valvuloplasty in neonates and children with severe aortic stenosis is to achieve the lower as possible gradient with the least degree of aortic regurgitation.Since oversized balloons  are associated with an increased risk of aortic regurgitation, precise measurements of aortic annulus are essential  to avoidAlso, recent data showed that percutaneous balloon pulmonary valvuloplasty under echocardiographic guidance seems to have the same results as standard valvuloplasty but with lower contrast load and radiation, which is of great importance in pediatric patients .Currently, PDA closure in extremely low birth weight infants relies almost exclusively on TTE guidance with high-frequency probes . PrematuDifferent measures are needed to help in device choice, such as PDA diameter at the aortic and pulmonary end, and PDA length . UsuallyAfter PDA device deployment, the presence of residual shunt, as well as potential left pulmonary artery and aortic obstruction must be assessed. A Doppler velocity greater than 2.5 m/s associated with aliasing at Color-Doppler and 2D images consistent with obstruction should advocate, if possible, device repositioning .in utero/life threatening at birth is growing , CT, magnetic resonance imaging (MRI), and TEE have gained an increasing importance in the interventional workflow. Advanced computing technologies and user-friendly interfaces allows efficient generation of high-quality 3D reconstructions from pre procedural or real time volumetric data sets to plan and guide interventions.Rotational angiography uses fluoroscopy C-arm rotation in concert with timed contrast injection to generate multiple 2D datasets that can be reconstructed into high resolution 3D models. Both the dynamic 2D rotational angiogram and 3D reconstruction provide valuable spatial information of the target lesion and relationships to adjacent anatomy such as the airways which is not available from biplane 2D angiography. Several studies have reported an additive diagnostic yield of 3D RA when applied in the evaluation of pulmonary vasculature following cavopulmonary connection in single ventricle patients, which led to changes in patient management –64. BecaApplication of 3D-RA during percutaneous pulmonary valve implantation (PPVI) enables complete evaluation of RV outflow tract morphology and calcification patterns and assessment of potential coronary or aortic compression during balloon inflation at the intended site of valve deployment . FurtherAn initial concern with 3DRA is the potential for additional radiation burden. However, published experience of 3DRA for various cardiac interventions have reported comparable or lower exposure rates to standard biplane angiographic acquisitions, particularly following dose optimization strategies , 68, 74.Fusion imaging is the overlay of 3D rendered volumes acquired from different imaging modalities on live fluoroscopy for procedural guidance. A pre-requisite for image fusion is the spatial and temporal alignment of images, a process termed image registration.Computed tomography (CT) is the most commonly used modality as the high-resolution acquisition of vasculature and airway allow for easy segmentation and registration. MR imaging has the advantage of avoiding additional radiation exposure and the ability to incorporate cardiac and respiratory motion during acquisition may improve image registration. Multiple approaches have been described for image registration, including automated 2D-3D registration in combination with fiducial markers, or manual refinement with spine, airways, catheter movement or cardiac silhouette as reference points , 75–78. Echocardiography- fluoroscopy fusion (EFF) overlays dynamic 2D/3D soft tissue information of the cardiac structure of interest on live 2D fluoroscopy. Distinct advantages of this fusion modality include the ability to show real time changes in anatomy during the procedure, monitor for complications, and comprehensive assessment of post-procedure outcomes, providing important feedback to the operator. Image registration is performed by tracking the movement of the transesophageal probe on fluoroscopy. The EFF system automatically match and align a computer-based model of the TEE probe with the fluoroscopic image of the probe, allowing continuous and instantaneous spatial registration of the two modalities each time fluoroscopy is activated. After registration, the 3D TEE volume (field of view cone) is displayed in the same anatomic alignment as the fluoroscopic projection. Anatomical ‘markers’ can be placed to label the structure of interest. The markers are visible in all views of the 3D TEE volume data and in spatially correlated locations on the fluoroscopic image. Other features including color overlay and 3D anatomic rendering additional valuable information to guide specific interventions. Such exposition of the target lesion/cardiac structure facilitates precise catheter manipulation for crossing of defects or positioning of devices and has been proven useful for ASD and VSD closure, specifically in fenestrated defects , 80, perDespite the advances in 3D imaging techniques, display of 3D data on conventional 2D screen hampers depth perception and appreciation of the complex spatial relations of cardiac structure. Advances in biomedical engineering have led to three-dimensional printing or additive manufacturing that bridges this gap through creation of a physical replica from CT and 3D RA data. The printed models allow true 3D visualization of anatomy , proceduDigital reality technologies have emerged as an alternative 3D visualization platform which can be used not only for planning, but also to assist execution of procedures . The abiMore recently, patient-specific computational models generated from 3D imaging have been developed for virtual planning of intervention and prediction of procedural outcome in pulmonary valve implantation and coarctation stenting. Using simulation methodologies such as finite-element and computational fluid dynamics, deformation of cardiac tissues and blood flow pattern in the heart can be modeled during virtual deployment of devices within the reconstructed surface anatomies –98. For In tandem with the growing diversity and complexity of percutaneous cardiac interventions, imaging must provide reliable visualization of cardiac anatomy to facilitate optimal planning and tailored treatment. 3D echocardiography and multimodality imaging can no longer be considered only as a luxury, but a daily clinical tool, playing a major role on today’s practice and the future to come.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.MA, S-LK, and XI: design and drafting of the manuscript. ZJ: study supervision. XI and J-BT: critical revision of the manuscript for important intellectual content. 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.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.


Transcatheter edge-to-edge repair (TEER) has developed from innovative technology to an established treatment strategy of mitral regurgitation (MR). The risk of iatrogenic mitral stenosis after TEER is, however, a critical factor in the conflict of interest between maximal reduction of MR and minimal impairment of left ventricular filling. We aim to investigate systematically the impact of device position on the post treatment hemodynamic outcome by involving the patient-specific segmentation of the diseased mitral valve.Transesophageal echocardiographic image data of ten patients with severe MR  were segmented and virtually treated with TEER at three positions by using a position based dynamics approach. Pre- and post-interventional patient geometries were preprocessed for computational fluid dynamics (CFD) and simulated at peak-diastole with patient-specific blood flow boundary conditions. Simulations were performed with boundary conditions mimicking rest and stress. The simulation results were compared with clinical data acquired for a cohort of 21 symptomatic MR patients  treated with TEER.2. Central device positioning resulted in a 14% smaller MVA than eccentric device positions. Furthermore, residual MVA is better predictable for central than for eccentric device positions (R2 = 0.81 vs. R2 = 0.49). The MVA reduction led to significantly higher maximal diastolic velocities  and pressure gradients  in spite of a mean flow rate reduction by 23% due to reduced MR after the treatment. On average, velocities were 12% and pressure gradients were 25% higher with devices in central compared to lateral or medial positions.Virtual TEER reduces the mitral valve area (MVA) from 7.5 ± 1.6 to 2.6 ± 0.6 cmVirtual TEER treatment combined with CFD is a promising tool for predicting individual morphometric and hemodynamic outcomes. Such a tool can potentially be used to support clinical decision making, procedure planning, and risk estimation to prevent post-procedural iatrogenic mitral stenosis. Mitral regurgitation (MR) is one of the leading acquired valvular heart diseases in western societies with an increasing prevalence in people over 65 years of age , 2. The The technique has first been proposed about 30 years ago by the Italian surgeon Ottavio Alfieri  as the AHowever, recurrence of MR and the risk of iatrogenic mitral stenosis (MS) are major issues and reduce the therapeutic effect –12. The TEER procedures, in contrast to surgical interventions, are performed on the beating heart and thus allow for real-time monitoring of hemodynamic parameters, such as left atrial pressure, residual regurgitation, and MPG. Since the hemodynamic characteristics under anesthesia or sedation might not be comparable to hemodynamics in an awake state or even under physical stress, drug-induced stress testing represents a valuable option to test hemodynamics with a TEER device in place. This is, however, only done if necessary in cases of very low stroke volume  and not A clinical routine of TEER interventions lacks planning tools for device placing and risk assessment, particularly for borderline cases. Planning tools should ideally not only take individual patient characteristics into account but be also able to predict post-interventional residual MVA and MPGs under different activity levels to estimate the risk of MS.Computational methods and image-based modeling provide tools to investigate several hemodynamic parameters on the basis of patient specific input data. Such approaches have, for instance, been applied to investigate left ventricular hemodynamic flow structures –24, the In this work, we want to investigate the influence of the device position on diastolic hemodynamic parameters with regard to iatrogenic stenosis at an individual level of treatment planning. Therefore, we systematically apply virtual TEER treatment in a cohort of 10 patients at three different positions with position based dynamics. Diastolic hemodynamic parameters at conditions of rest and moderate stress are subsequently simulated by means of a low-complexity computational fluid dynamics (CFD) approach . The simThe workflow of this study is displayed in n = 2 female, MR grade III, NYHA class III), diagnosed with severe primary mitral regurgitation, was retrospectively analyzed. An aspired share of 50% female cases within the cohort could not be achieved due to a limited database. All patients showed a primary mitral insufficiency without any further heart valve pathology and underwent surgical mitral valve repair since they were not considered high-risk patients. As no suitable 3D TEE data of a patient cohort receiving TEER data was available at the time of this study, we developed this workflow on a cohort with the same pathology but different treatment. A cohort of 10 patients  who received mitral TEER to treat MR of various causes . Mitral orifice areas were evaluated by planimetric measurements from 3D TEE images. Maximum and mean velocity and mitral pressure gradients were measured using continuous wave Doppler echocardiography images. All TEE images were acquired peri-operatively in routine practice with a GE Vivid E95 Ultrasound machine .For plausibility check, the simulation results are compared to clinical routine data of 21 patients . Imaging was performed with a synchronized electrocardiogram. Volumetric TEE sequences that were used for segmentation had a time resolution of 23 ± 5.5 frames per cycle. The automated LV-Analysis tool of Tomtec Arena was used to segment the LV over an entire cycle from 4D TEE images. Manual corrections were applied at the end-diastolic phase to improve the accuracy of the automated segmentation. A segmentation of the mitral valve in the early diastolic phase was obtained by manual adaptation of the automated valve segmentation during systole by means of the 4D MV-Assessment tool (Tomtec Arena). The MV commissure definition results from the automated systolic segmentation of Tomtec and was not changed during manual adaption. Only the leaflet reconstruction of the initial segmentation was adapted to the open state in a frame during diastole by moving the segmentation spline until it overlapped the leaflets.Pre-operative TEE images of the simulation cohort acquired with a GE Vivid E9 Ultrasound machine  were processed using the software Both MV and LV segmentation were exported as triangulated surface meshes in the STL format. The initial segmentation of Tomtec has a low spatial resolution. To enhance surface quality, the MV geometries are remeshed and smoothed, after which they have an average edge length of 1.3–1.8 mm. Detailed mesh statistics can be found in the r, φ, z) in which the height axis (z-component) was aligned with the normal vector of the annulus plane  | φ∈}) and posterior leaflets  | φ∈}) and into the six sectors {A, P}{1, 2, 3}. The boundaries between the sectors were located at To perform an automated virtual TEER at comparable positions, commissure points of the segmentation were added as landmarks to each valve data set. This information was used to divide the reconstructed valve surface into anterior and posterior segments and into sectors A1, A2, A3, P1, P2, and P3 see . For thi segment . Three dThe virtual TEER process is simulated by means of our previously developed approach –36. The t = 10−4 s was applied for temporal discretization. Blood was modeled as an incompressible non-Newtonian generalized Carreau-Yasuda fluid with dynamic viscosity (Equation 3) with η∞ = 0.0035Pa·s, η0 = 0.16 Pa·s, λ = 8.2 s, n = 0.2128, a = 0.64 .Mesh base size was set to 1.0 mm with a refinement in the MVA down to 0.25 mm to ensure sufficient spatial resolution of expected detachment phenomena and acceleration at the leaflet tips. The conducted mesh independence study can be found in the Tomtec Arena was used to obtain the volume curve as exemplarily shown for Patient 2 in V between two consecutive segmentations Δt . The MVA is an important indicator for assessing the suitability of a TEER procedure for a patient since guidelines recommend to only consider patients with a MVA>4 cmfor TEER . During for TEER . Maximumfor TEER  and the t-test was used to test for significant differences within normally distributed parameter differences, while the Mann–Whitney U and Wilcoxon signed-rank tests were used for testing non-normally distributed parameter differences. Paired tests were used to compare differences between pre- and post-treatment and between different device positions. All tests used a standard significance level of 0.05.Statistical analysis of simulated and clinical data was performed using IBM SPSS Statistics 28 software . Mean and SD were reported for normally distributed parameters as assessed by the Shapiro-Wilk test due to the high statistical power of the test and due to the small size of both cohorts. Otherwise, median and interquartile [IQR] ranges were used. The two-tailed student's In the following, results of the simulations before and after virtual TEER under conditions of rest and stress are presented and compared to clinical routine data. First, the influence of virtual TEER on the MVA was analyzed. Furthermore, the results of image data analysis delivering the boundary conditions for CFD and hemodynamic results of the CFD simulations themselves were investigated. 2 and reduce to 2.56 ± 0.63 cm2 after virtual TEER when averaging over all device positions. Comparison of the remaining MVA after virtual device placement at different positions shows that central positions lead to a significantly stronger reduction of MVA than eccentric positioning of the device (paired t-test) at either lateral (p = 0.002) or medial (p = 0.035) segments of the leaflets. A virtual TEER at the A1-P1 segments  leads to a mean MVA of 2.65 ± 0.68 cm2 and A3-P3  leads to a mean MVA of 2.72 ± 0.62 cm2. This is a reduction of MVA to 35 and 36% of the original MVA, respectively. Central device positioning at segments A2-P2 reduces the MVA to 31%, measuring 2.30 ± 0.58 cm2. This leads to an average difference of 0.35–0.42 cm2 between central and eccentric device positions (see 2) according to  presented in this study are provided as open data on figshare: The studies involving human participants were reviewed and approved by Ethics Committee of Charité—Universitätsmedizin Berlin. The patients/participants provided their written informed consent to participate in this study.KV and LG: conceptualization. KV and FB: data curation. KV, LW, and LG: formal analysis, methodology, and writing original draft. LG, UL, TK, and AH: funding acquisition and supervision. KV and LW: visualization. KV, FB, MR, and MK: investigation. All authors: review and editing, contributed to the article, and approved the submitted version.This work was part of the projects EurValve , DSSMitral, and MINIMAKI, each funded by the German Federal Ministry of Education and Research (Grant nos. 03VP00851 and 16SV8649).Author FB received grant support from Abbott Laboratories . The remaining 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.


The study shows that a pragmatic approach to hormonal assessment (no chronic therapy modification) may reveal patients with AAS. Screening for this subclinical PA presentation is probably more effective with a permissive ADRR than UAldE in such a setting.In recent years, research has emphasized the significance of mild clinical and biochemical presentations of primary aldosteronism (PA) that do not meet current diagnostic criteria of the syndrome. In this study, we assessed the prevalence of autonomous aldosterone (Ald) secretion (AAS), defined as a positive (>1.2 ng/dL/mIU/L) Ald-to-renin ratio (ADRR) combined with unsuppressed Ald (>4 ng/dL), and its associations with blood pressure (BP), cardiac function, and common carotid artery (CCA) intima-media thickness (IMT) in patients with incidentally discovered adrenal adenomas (AI), who were either normo- or hypertensive but had no other cardiovascular disease. Among 332 AI patients hospitalized between November 2018 and December 2019, 63 study participants were recruited (26 normo- and 37 hypertensive), who underwent hormonal examinations, 24 h ambulatory BP measurement, transthoracic echocardiography, and CCA IMT assessment without altering chronic medications. AAS was found in approximately 25% of subjects (seven normo- and nine hypertensive); urinary aldosterone excretion (UAldE) exceeded 10 ug/day in none of the subjects. The left ventricular mass index correlated positively with UAldE in non-diabetic patients ( The recommended method of screening for primary aldosteronism (PA) is determining the aldosterone-to-renin ratio . It is anT) and normokalemia but biochemically proven Ald excess, and (2) patients with HT and normokalemia who meet PA screening but not confirmatory test criteria, provided Ald is not suppressed (in both cases).In fact, accumulating evidence indicates the current approach toward PA does not encompass the whole spectrum of renin-independent excess aldosteronism ,4. RecenWhile a fully objective assessment of Ald secretion requires therapy modification to limit the influence on the renin–angiotensin–aldosterone system (RAAS), this requirement frequently dissuades clinicians from ordering screening — research shows less than 10% of eligible patients undergo it both in primary care and specialist settings ,7. FurthIn this cross-sectional study, we examined the prevalence of AAS and its associations with blood pressure (BP), cardiac function assessed by transthoracic echocardiography (TTE), and intima-media thickness (IMT) among patients with incidentally discovered adrenal tumors (AI) with radiological features of adrenocortical adenomas and/or hyperplasia, who were either normo- or hypertensive but had no other cardiovascular disease (CVD). Subjects were recruited from November 2018 through December 2019 among patients with adrenal incidentalomas (AI), as defined in the European Society of Endocrinology guidelines }. LVM was indexed to body surface area (BSA) calculated with the Du Bois formula: BSA = 0.007184 × W0.425 × H0.725 : LVMI = LVM/BSA. Left atrium volume (LAV) was calculated by the disk summation technique (modified biplane) from the apical four and two chamber views. LAV was indexed to BSA: LAVI = LAV/BSA.TTE recordings were performed with a Vivid E9 GE device with an M5Sc transducer in accordance with the European Association of Cardiovascular Imaging and the American Society of Echocardiography recommendations . Study p2, (2) tricuspid regurgitation (TR) velocity > 2.8 m/s, (3) E/e’ > 14, and (4) septal e’ < 7 or lateral e’ < 10 cm/s . FuThe effect of hypotensive drugs, including beta blockers, might also partly underlie surprising negative correlations between Ald and BP in 24 h monitoring. Their action may have triggered Ald release dependent on ACTH in the morning hours, during which blood was collected.A correlation between Ald and LVMI implicates the mineralocorticoid in LV hypertrophy in patients without overt PA. More refined measures of abnormal cardiac function  might provide better insight into the adverse effects of AAS.While the deleterious effects of overt PA are widely appreciated, AAS is currently not an established disorder; mild PA forms remain largely unrecognized . Our stuSuch research has been accumulating in the case of MACS . In our