In the adjusted logistic regression, LAVi min, LAEF, LV ejection fraction, and LVGFI showed the most robust association  powered by artificial intelligence provides accurate left chamber quantification in good accordance with cardiac magnetic resonance and has the potential to revolutionize our clinical practice. Aims. To evaluate the association and the independent value of dynamic heart model (DHM)-derived left atrial (LA) and left ventricular (LV) metrics with prevalent vascular risk factors (VRFs) and cardiovascular diseases (CVDs) in a large, unselected population. Materials and Methods. We estimated the association of DHM metrics with VRFs  and CVDs , stratified by prevalent disease status: participants without VRFs or CVDs , with at least one VRFs but without CVDs, and with at least one CVDs. Results. We retrospectively included 1069 subjects . When comparing VRFs with the healthy, significant difference in maximum and minimum indexed atrial volume (LAVi max and LAVi min), left atrial ejection fraction (LAEF), left ventricular mass/left ventricular end-diastolic volume ratio, and left ventricular global function index (LVGFI) were recorded ( Despite the well-known limitations , traditiYet, many of these issues are now solved by automated three-dimensional echocardiography 3DE) [DE [3]. RAccordingly, we sought to evaluate the association of DHM-derived LA and LV metrics with prevalent VRFs and CVDs in a large, unselected population-based cohort and the independent value of LA metrics over LV structure and function measures. Secondarily, to be closer to clinical practice, we reported the values of principal and derived DHM metrics in the healthy population for male and female subgroups, and the intra- and interoperator variability in a random group with heterogeneous acoustic window and case mix.The study population comprised patients aged >18 years who underwent standard transthoracic Doppler echocardiography for any indication from 14 September 2020 to 9 November 2021 at Modena University Hospital’s echocardiography laboratory. Criteria for enrollment included (1) age > 18 years and (2) complete resting 2D and 3D echocardiographic assessment. We excluded patients with unsatisfactory images—the margins were not seen well and thus deemed untraceable, and patients on dialysis since large fluid shift patients may cause significant extemporaneous differences in LA and LV measurements. Age, sex, height, weight, body surface area (BSA), cardiac rhythm, clinical indications, and history of cardiovascular diseases were recorded at echocardiography. The study protocol followed the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the local ethic committee .A complete 2D and 3D transthoracic echocardiographic examination was performed, according to current guidelines ,10, usinBriefly, after setting gain, time-gain compensation, and depth on 2D images, a single-beat acquisition mode from the apical 4-chamber view was used to acquire 3D wide-angle datasets. By changing sector width and image depth, the 3D frame rate was optimized. All the acquisitions were performed by operators fully trained in echocardiography with long-standing experience with the 3D technique and trained on echocardiographic datasets focusing on what constitutes adequate automated analysis. The novel vendor software simultaneously detects LV and LA endocardial surfaces using an adaptive analytics algorithm, which uses knowledge-based identification to orient and locate cardiac chambers and patient-specific adaptation of endocardial borders from which LV and LA volumes are derived directly without geometrical assumptions. Using the automated DHM program, which automatically detects LV endo- and epicardial borders at the end-diastole, 3D-LV mass was analyzed, enabling direct LV mass thickness. While it is possible to correct the LV and LA endocardial–epicardial borders at the end-diastole and and-systole, previous studies have shown that LV volumes ,7 and LVWe considered the following DHM measures: LV end-diastolic volume indexed to BSA (EDVi), LV end-systolic volume indexed to BSA (ESVi), LV ejection fraction (LVEF), LV stroke volume indexed to BSA (SVi), LA maximum volume indexed to BSA (LAVi max), LA minimum volume indexed to BSA (LAVi min), LA ejection fraction (LAEF), automatically calculated as LA maximum volume-LA minimum volume/LA maximum volume), LV mass indexed to BSA, LV mass: LV end-diastolic volume ratio (LVM/LVEDV). We considered the LV global function index (LVGFI) as an additional measure of the LV function originally described with cardiac magnetic resonance . PreviouAll 3D echocardiography images were analyzed online using the larger default boundary detection sliders . This setting defines diastolic and systolic contour positions within the myocardial wall ranging from 0 to 100, 0 being the most inner endocardial contour toward the LV cavity and 100 being the most outer endocardial contour towards the myocardial wall. To the best of our knowledge, there are no specific recommendations about this feature, and the decision is left to the single image laboratory. We deliberately decided to apply these fixed threshold borders settings because they were the ones used in previous validation studies, and they are closer to the settings of CMR . All meaWe considered the following VRFs: arterial hypertension, diabetes, and CVDs : atrial fibrillation, stroke, ischemic heart disease, cardiomyopathies, >moderate valvular heart disease/prosthesis. To ascertain prevalent VRFs and CVDs, we referred to baseline verbal interviews, patients’ documentation, or records in our institutional database. The diagnosis of these conditions was formulated according to current guidelines.To assess the reproducibility of DHM measurements, intraoperator and interoperator variability was evaluated in a subset of 22 randomly selected patients. Two loops from the same patient were acquired and analyzed by a senior physician (A.B.) to evaluate intraoperator variability. Another loop from the same patient was acquired by a junior physician (A.A.) blinded to the previous measurements to assess interoperator variability. All the analyses were performed without contour adjustment .Data are shown as counts and percentages for categorical variables. Mean ± SD or median and IQR have been used for continuous variables according to the normality or non-normality of the distribution. Comparisons across groups were made using Chi-square or Fisher’s exact test for categorical variables. For continuous variables, parametric or nonparametric tests were utilized according to the normality of the distribution. In particular, independent samples t-test or Mann–Whitney U test was applied for two sample comparisons and analysis of variance or Kruskal–Wallis H test was the choice when more than two groups were analyzed. The independent association of the DHM metrics with VRFs and prevalent CVDs was assessed by multivariable logistic regression models modeling each DHM metric adjusted for confounders (age and sex). Intra- and interoperator variability was assessed by performing Pearson’s linear correlation and Bland–Altman analysis (bias and limits of agreement (LOA)) and then reliability was assessed using the interclass correlation coefficient (ICC) and coefficient of variation (CoV).p < 0.05 were considered statistically significant. All analyses were performed using SPSS version 28.0 for Windows . All tests were two-tailed. Values of A total of 1069 participants for whom DHM data were available were included. The cohort had a median age of 62 [IQR 49–74]; 50.6% were women. The participants with hypertension and diabetes were 37% and 10.9%, respectively. The proportion of participants with prevalent atrial fibrillation, stroke, ischemic heart disease, cardiomyopathies, and >moderate valvular heart disease/prosthesis at the time of DHM was 16%, 4.1%, 14.7%, 11.4%, and 15.7%, respectively .The comparison of DHM metrics among the subsets of participants (i) without VRFs or CVD , (ii) with VRFs, but without CVD, and (iii) with CVD is displayed in In the multivariable logistic regression adjusted for age and sex, none of the DHM metrics were significantly associated with prevalent VRFs when assessing healthy and VRFs cohorts. On the contrary, EDVi, ESVi, LVEF, LAEF, LV mass indexed, LAVi max, LAVi min, and LVGFI were independently associated with prevalent CVDs in the adjusted analysis . LAVi miIntra- and interoperator variability was assessed in a sample of 22 random patients from the overall population. Of note, this random group had different acoustic window quality  and a heterogeneous case mix, reflecting the complexity of the overall population , Our findings add to the literature by demonstrating for the first time the association of DHM metrics with prevalent VRFs and CVDs in a large population of consecutive subjects who underwent echocardiography for any indications. The main findings were: (1) when considering the LA parameters, significant differences between patients with VRFs and healthy subjects were reported; (2) about LV parameters, there was a stepwise decline in LV function and a significant worsening in terms of EDVi, ESVi, and LV mass when considering CVDs; (3) in the multivariable logistic regression analysis, LVEF, LAEF, LAVi min, and LVGFI have the more robust association with prevalent CVDs. Of note, we measured an ICC greater than 90% for most of the parameters and acceptable coefficients of variance with less consistent intra- and interoperator reliability for the LA morphological and functional parameters.The LA is widely recognized for being extremely sensitive to LV hemodynamic changes ,18. AlteOne notable result of the present study is that LAVi min and LAEF have the most robust association with prevalent CVDs compared to LAVi max. It may be argued that LAVi max depicts the severity and chronicity of LV filling pressure, which is supported by prognostic data . On the It is important to point out that DHM provides two good LA parameters quickly at the same time , allowing for interesting clinical applications considering that the LA takes time to remodel  and may These findings should encourage echocardiographers to incorporate the LAEF evaluation by using 3DE-dedicated software packages. We believe that the feasibility and the clinical implications of the LAVi min and LAEF with DHM support the clinical need to incorporate such novel measures, in addition to the guideline-recommended LA assessment by LAVi max, into a more comprehensive evaluation of LA structure and function. Surprisingly, a recent European Association of Cardiovascular Imaging (EACVI) survey showed that only 10% of centers use 3DE to assess LA volumes and that 68% of centers did not use a measure of LA function .Considering LV parameters, we showed that LVGFI and LVEF provided a more robust association with CVDs, with LVGFI showing the most consistent results. In recent years, the sensitivity and specificity of LVEF for risk stratification have been questioned  and noveGiven that data for defining reference values for DHM are currently unavailable, we also analyzed the subgroup of healthy subjects in the present study. We found that the mean LV volumes assessed by DHM were larger than contemporary commercial 3DE automated ultrasound imaging systems values ,43 and mThe comparison between different imaging techniques, especially when comparing echocardiography and CMR, requires considering the “imaging quality issue” because 3DE deeply relies on good image acquisition. In our study, we aimed at the highest imaging quality, and the elevated frame rate of the 3D dataset showed that only high-quality data have been analyzed. Our group has already addressed this issue in a recent paper in which 201 consecutive patients underwent DHM echocardiography and 22% were excluded because of an inadequate acoustic window for 3D measurements, and 7% for problematic geometric assumptions . These dA more appropriately powered study with the capacity to examine associations would allow for a more granular disease-specific subanalysis.Due to the observational nature of this study, a significant limitation is the lack of detailed history of other significant factors potentially affecting cardiac remodeling . This fact may have resulted in the nonsignificant association in the regression analysis. However, diabetes and hypertension are the VRFs most likely to be independently associated with DHM metrics. Indeed, recent data from UK Biobank participants  assessedMoreover, residual confounding or reverse causation cannot be ruled out; nonetheless, the primary goal of this study was to characterize associations rather than make causative inferences.We do not account for LV and LA global longitudinal strain and N-terminal pro-B-type natriuretic peptide. Strain, however, necessitates additional specialized tracking software since it is not included in the basic DHM on ultrasound machines and reporting systems.Finally, DHM was not performed on top of conventional 2DE quantitative morphometric evaluation for comparative analysis. However, since the DHM has been at our disposal, 2DE volumetric analysis is no longer routinely performed in our institution.The present data suggested that novel 3DE left heart chamber metrics by DHM such as LAEF, LAVi min, and LVGFI can refine our echocardiographic disease discrimination capacity. The following steps will require assessing the associations between DHM metrics with clinical outcomes in additional cohorts and clinical scenarios.


The LVEDV (p = 0.001) and esEI (p < 0.009) were independent predictors of PVR. Systolic pulmonary arterial pressure (PAP) (p < 0.001), diastolic PAP (p < 0.001), mean PAP (p < 0.001), right atrial pressure (p < 0.023), and PVR (p < 0.001) were significantly higher in the high esEI group than in the low esEI group. The esEI was a simple predictor of CTEPH severity.The usefulness of the parameters of biventricular function simultaneously measured using enhanced multi-detector computed tomography (MDCT) pulmonary angiography in patients with chronic thromboembolic pulmonary hypertension (CTEPH) has not been clarified. This study aimed to verify the correlation between left and right ventricular (RV) parameters and pulmonary vascular resistance (PVR). Patients who underwent enhanced MDCT before diagnostic right heart catheterization at Nagoya University Hospital between October 2014 and April 2021 were enrolled. The correlation of biventricular function and volume parameters with PVR was assessed. Eighty patients were retrospectively analyzed. Patients’ mean age was 65 ± 13 years, mean PVR was 9.1  Wood units, and mean end-systolic eccentricity index (esEI) was 1.76 ± 0.50. RV end-systolic volume (ESV) ( Chronic thromboembolic pulmonary hypertension (CTEPH) is a phenotype leading to pulmonary hypertension (PH) and is defined as group 4 according to the Nice clinical classification . As the The prognosis of patients with CTEPH who do not have an indication for pulmonary endarterectomy has been very poor so far ; howeverRight ventricular (RV) function is a predictor of prognosis in patients with PH ,9,10,11.This study was approved by the Human Research Ethics Committee of Nagoya University Hospital (number: 2021-0369).This single-center, retrospective, observational study was conducted at Nagoya University Hospital in Japan. Consecutive patients who underwent enhanced MDCT before their diagnosis of CTEPH between October 2014 and April 2021 were enrolled in this study. CTEPH was diagnosed using standard diagnostic criteria: a mean pulmonary arterial pressure (mPAP) ≥25 mmHg, pulmonary arterial wedge pressure (PAWP) ≤15 mmHg according to right heart catheterization (RHC), and abnormalities on a ventilation/perfusion scan or residual thrombus of the PA on CT or transcatheter pulmonary angiography after proper term anti-coagulant therapy [RHC was performed using a standard protocol under ambient air with a 6-French Swan-Ganz catheter . The puncture site was the internal jugular vein in all patients under local anesthesia rather than general anesthesia. The transducer was placed at mid-chest level. The PAP, right atrial pressure, RV pressure, PAWP, and cardiac output (CO) were measured. A thermodilution method was used to provide CO. The PVR was calculated as follows: (mean PAP–PAWP)/CO.ECG-gated cardiac scans were performed using dual-source CT  with a tube voltage of 120 kV, collimation of 64 × 0.6 mm, and rotation time of 0.28 s/rotation. The helical pitch was adjusted according to the heart rate, and the automatic tube current modulation was set to a quality reference mAs/rotation of 180. The contrast medium was intravenously administered using a dual-head power injector , followed by 20 mL of saline at a rate of 4 mL/s. The injection protocol was optimized according to body weight: <40 kg, 80 mL at a rate of 3.3 mL/s, 300-mg iodine/mL iopromide; 40–55 kg, 96 mL at a rate of 4 mL/s, 320-mg iodine/mL ioverso; and ≥55 kg, 96 mL at a rate of 4 mL/s, 370-mg iodine/mL iopamidol. Following the refined CT scan protocol in the pulmonary parenchymal phase using a bolus-tracking method (threshold of 80 HU in the ascending aorta) [Biventricular functions were analyzed using a three-dimensional image analysis application . Based on the multiphase reconstruction CT images, end-diastole was defined as 0% of the RR interval, and end-systole was defined as the minimal ventricular volume. The contours of the ventricular lumens at end-diastole and end-systole were semi-automatically or manually traced, and end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) were automatically calculated using Simpson’s method a–c. SincThe LV end-diastole index (edEI) and end-systole eccentricity index (esEI) were measured on short-axis images at the level of the papillary muscles as follows: EI = D2/D1 d.Continuous variables are presented as mean ± standard deviation or as median and interquartile range. Categorical variables are presented as number and percentage.In the main analysis, the correlation between PVR of RHC and biventricular function parameters of CT was analyzed using Spearman’s rank correlation coefficient. Multivariate analysis was performed using multiple regression analysis. Independent variables of the biventricular function parameters were selected according to their significance in the univariate analysis. The RV ejection fraction was excluded from the multivariate model owing to multicollinearity.t-test, whereas those without a normal distribution were analyzed using Wilcoxon’s signed-rank test. Supplemental data were analyzed using Spearman’s rank correlation coefficient and the multi-regression test. The edEI and RVEDV were excluded from the multivariate model because these parameters were different from the esEI in the cardiac phase.In the sub-analysis, to verify patient characteristics, the esEI was divided into two groups (high esEI group and low esEI group) based on a median of 1.64, and patient characteristics were compared between the two groups. Variables with a normal distribution were analyzed using the independent samples p-value < 0.05 was considered statistically significant.Statistical analyses were conducted using the SPSS statistical software program  or Stata version 17 , and a p = 0.007), RVCO , RVEF , LVEDV , LVESV , LVCO , edEI , and esEI  were significantly correlated with PVR. In multi-regression analysis, the LVEDV (p = 0.001) and esEI (p = 0.009) were independent predictive factors of PVR.All patients were treated with warfarin or direct oral anticoagulants, and none of the patients were treated with previous pulmonary vasodilators. The interval from enhanced MDCT to RHC was 26  days. Hemodynamic parameters obtained by RHC were as follows: mPAP, 41.2 ± 10.5 mmHg; CO, 3.9 ± 1.0 L/min; and PVR, 9.1  Wood units . The bivp = 0.017) and brain natriuretic peptide (BNP) levels were higher (p < 0.001) in the high esEI group than in the low esEI group. The systolic pulmonary arterial pressure (p < 0.001), diastolic pulmonary arterial pressure (p < 0.001), mPAP (p < 0.001), right atrial pressure (p < 0.023), and PVR (p < 0.001) were significantly higher in the high esEI group than in the low esEI group. Volumetric-enhanced MDCT revealed that the RVEDV (p < 0.001) and RVESV (p < 0.001) were larger, whereas LVCO (p = 0.003) were smaller in the high-esEI group than in the low-esEI group. The RVEF (p < 0.001) and LVEF (p = 0.013) were lower in the high esEI group than in the low esEI group. Furthermore, the independent factors related to the esEI were the RVESV (p = 0.001), LVCO (p = 0.038), and LVEF (p = 0.033) in multivariate analysis  the esEI and LVEDV, both of which were simultaneously measured during diagnostic enhanced MDCT pulmonary angiography, were significantly correlated with PVR; and (2) patients with a high esEI had more severe hemodynamic parameters and biventricular function, and the esEI was significantly correlated with the LVCO, LVEF, and RVESV.Generally, it is difficult to estimate the severity of PH in patients. Many factors in categorized risk stratification for patients with idiopathic or heritable pulmonary arterial hypertension (PAH), recommended by the European Society of Cardiology, are closely related to RV function, such as BNP levels and CO . AlthougAccurate estimation of RV function is difficult because of the complex anatomy of the right ventricle, which is anatomically separated into three segments: inflow, apex, and outflow tract . In addi7. In contrast, it has heightened sensitivity to elevated afterloads, which leads to RV dilation and hypertrophy, and eventually leads to pump failure. When the right ventricle maladapts, RVEF and end-systolic elastance to effective arterial elastance rate decrease, and RVEDV increases, resulting in increasingly more dilation of the right ventricle [In the present study, the esEI and LVEDV were significantly correlated with PVR in multivariate analysis. In other words, the severity of CTEPH depends on LV deformity and volume, but not the right ventricle. In terms of compliance, the right ventricle, which has thinner walls than the left ventricle, demonstrates good tolerability to increasing preloadentricle ,19. Prolucg) was correlated with RV pressure [ucg was correlated with hemodynamic parameters obtained by RHC and associated with PH outcome measures, such as PH-related hospitalization, medical therapy escalation, and increased BNP levels [UCG was previously verified in many studies on PH; however, the esEIs measured by MRI (esEIMRI) and CT (esEICT) were not adequately verified in PH, especially CTEPH. Although the accuracy of esEIucg depends on the angle and image quality, there are few dispersions in esEIMRI and esEICT. The esEIMRI predicted PAH with a high sensitivity of 91.9% and was an independent predictive factor of vital prognosis [MRI was significantly correlated with the mPAP, and the RVEF was negatively correlated with the edEI in patients with congenital heart disease, such as atrial septal defect and tetralogy of Fallot [MRI was proven to be useful in patients with PAH; however, PVR was not evaluated in either study. The negative correlation between edEICT and RVEF is consistent with the results of the present study (CT, even though enhanced MDCT is performed to estimate localization of the thrombus and suitability for surgical intervention in patients with CTEPH. Herein, the esEICT simultaneously measured during MDCT pulmonary angiography was a predictive factor for PVR. This is a great advantage of enhanced MDCT for measuring biventricular function and thrombus localization. It is not necessary to perform MRI to measure ventricular function. Additionally, early estimation of PVR leads to early preparation of pre-interventional pulmonary vasodilators, the so-called pretreatment and treatment for RV failure. The esEICT was significantly correlated with the LVCO, LVEV, and RVESV. Ventricular interdependence has not yet been clarified. Although the esEICT is a simple LV deformity index, the LV volume and function as well as the RV volume are influenced by the shared septum. The esEICT may cast new light on the exploration of ventricular interdependence.In the present study, the LVEDV and esEI were found to be independent predictors of PVR. Calculating the LVEDV is time-consuming and requires dedicated post-processing software, expert technicians, and time for analysis, whereas the esEI is a very simple and practical parameter that can be easily measured in everyday clinical practice if an ECG-gated cardiac scan is performed. In general, the esEI is measured using echocardiography. The esEI obtained by echocardiography (esEIpressure ,21 and ipressure . FurtherP levels . The esErognosis . The esEf Fallot . The esEnt study . A few rCT was not compared between the esEIUCG and erEIMRI groups. The comparison of accuracy and reproducibility between echocardiography, MRI, and CT is a future task. Third, although enhanced MDCT was performed at the maximal respiratory level to extend the PA, the extent of maximal inspiration could be biased because venous return and the RV volume were reduced during inspiration. Fourth, there was an interval between the enhanced MDCT and diagnostic RHC. If the hemodynamic parameters changed during the interval, this might have affected the results. Lastly, inter- and intraobserver biases were not verified because the similarities of accuracy and reproducibility between volumetric enhanced MDCT and MRI have been proven in a meta-analysis.The present study has several limitations. First, the size of the study population was small because patients from only a single PH center at Nagoya University Hospital were enrolled. Therefore, the results of the statistical analysis should be carefully interpreted. Second, the esEICT is a simple predictor and may be an important index for determining whether medical treatment before intervention is needed in patients with CTEPH.CTEPH severity was predicted using the LVEDV and esEI simultaneously measured during enhanced MDCT pulmonary angiography. The esEI was reflected by the LV volume and function, as well as the RV volume. Estimating the LV volume and function is essential in patients with CTEPH. In particular, the esEI


Having a new and more precise definition of BrS, based on its cardiomyopathic component, may be crucial to meliorate the current clinical management of patients, at (i) diagnostic, (ii) prognostic, and (iii) therapeutic levels: (i) diagnostic, since specific tests may be added to the current standards of BrS to identify associated arrhythmogenic substrates; (ii) prognostic, since multiple factors from an extended diagnostic workup may be associated with an increased arrhythmic risk , subsequently improving the patient selection for a primary prevention ICD implant; (iii) at therapeutic levels, since the identification of unexpected substrates may turn into a significant change in the current treatment practice.Brugada syndrome (BrS) is an inherited autosomal dominant genetic disorder responsible for sudden cardiac death from malignant ventricular arrhythmia. The term “channelopathy” is nowadays used to classify BrS as a purely electrical disease, mainly occurring secondarily to loss-of-function mutations in the α subunit of the cardiac sodium channel protein Nav1.5. In this setting, arrhythmic manifestations of the disease have been reported in the absence of any apparent structural heart disease or cardiomyopathy. Over the last few years, however, a consistent amount of evidence has grown in support of myocardial structural and functional abnormalities in patients with BrS. In detail, abnormal ventricular dimensions, either systolic or diastolic dysfunctions, regional wall motion abnormalities, myocardial fibrosis, and active inflammatory foci have been frequently described, pointing to alternative mechanisms of arrhythmogenesis which challenge the definition of channelopathy. The present review aims to depict the status of the art of concealed arrhythmogenic substrates in BrS, often resulting from an advanced and multimodal diagnostic workup, to foster future preclinical and clinical research in support of the cardiomyopathic nature of the disease. Brugada syndrome (BrS) is an inherited autosomal dominant genetic disorder, first described in 1992 [Current international guidelines ,4 agree SCN5A gene, encoding the α subunit of the cardiac sodium channel protein Nav1.5, responsible for the initial upstroke of the action potential [Despite recent advances, the pathogenetic mechanisms of the disease remain not fully understood. BrS had been initially proposed to be a primary disease functionally involving impairments in the electric potential transmission. BrS was defined as a channelopathy, due to the association of the disease genotype with loss-of-function mutations in genes encoding subunits of the cardiac ion channels . A consiotential . This haotential .Nevertheless, several studies suggested that subtle structural or microscopic abnormalities may actually take place in BrS, including dilation of the right ventricular outflow tract (RVOT), localized inflammation, and fibrosis ,10. ThesThe disclosure of concealed substrate abnormalities in BrS may be the answer to the perception of BrS as more than a pure channelopathy, potentially enabling an improvement in the current diagnostic, prognostic, and therapeutic workflow. The present review aims at exploring this concept while providing an updated description of cardiomyopathic changes associated with the disease, from pathophysiological, diagnostic, and prognostic viewpoints.SCN5A gene underlying BrS was reported in 1998 [SCN5A gene [+ current and a consequent shortening of the depolarization phase of the action potential [At the time that the first genetic alteration in the  in 1998 , highligN5A gene , leadingotential .SCN5A alterations in the prediction of patients’ arrhythmic risk. Indeed, carriers of a deleterious variant in the SCN5A gene show a spontaneous BrS ECG [Some studies suggested a role for  BrS ECG  and a mo BrS ECG .SCN5A gene [Overall, about 20% of cases are caused by rare coding variants in the N5A gene ,17, whicN5A gene ,19,20. CN5A gene ,41,42,43N5A gene . The curThe limited number of BrS cases with a clear monogenic inheritance has pointed toward new hypotheses of a more complex genetic architecture of the disease, involving multigenic inheritance and a polygenic risk score that can influence penetrance and risk stratification . RecentlIndeed, polygenic risk score analyses based on several susceptibility variants demonstrate a cumulative contribution of common risk alleles among different BrS patients, as well as genetic associations with cardiac electrical traits in the general population, thus supporting the concept of “genomic arrhythmia” .Moreover, the recent findings also highlight that genes encoding structural proteins or cardiac transcription factors are associated with the BrS phenotype, thus strengthening the hypothesis of overlap with structural cardiomyopathies ,45.SCN5A has been published in symptomatic female patients with BrS compared with male patients, and an even higher prevalence in females with BrS with arrhythmic events [SCN5A in women may be a risk factor, perhaps by overcoming a “protective” environment [Clinical BrS manifestations are more common in adults, and despite autosomal inheritance, they are eightfold more frequent in males than in females . To datec events  suggestiironment .Overall, although different genetic approaches have been adopted, the characterization of BrS molecular bases remains limited. The identification of new candidate genes and risk factors can lead to a better definition of BrS pathogenic mechanisms, allowing an increase in diagnostic sensitivity and the improvement of family and clinical management and risk stratification.Cardiomyopathies are uniformly characterized by the identification of either structural or functional myocardial abnormalities via imaging techniques. Although most patients with BrS display no remarkable alterations on a transthoracic echocardiogram (TTE) or via cardiac magnetic resonance (CMR) imaging , some ECAlthough the classical echocardiography parameters have a limited yield in BrS, new techniques including strain and speckle tracking ,66 have SCN5A mutation, with wider involvement of the RV than the LV [SCN5A mutations [CMR is an accurate and reproducible tool for estimating both left ventricular (LV) and RV volumes and is now considered the gold standard technique for cardiomyopathies ,4. Althon the LV  as obsern the LV  allowed utations . In partutations , accountFrom the first characterizations of the ECG pattern, structural alterations, such as fibrosis, fibrolipomatosis, and RV cardiomyopathic changes, were described in patients with apparent idiopathic ventricular fibrillation (VF) . As receSCN5A mutations displayed more cardiomyopathic changes. Remarkably, many patients were positive for intracardiac viral genomes. The authors suggest that the classic BrS ECG pattern is not a marker of a specific syndrome, but rather an electrical expression of RV structural abnormalities which may be the outcome of genetic, infective, and inflammatory conditions. In another study, RVOT endomyocardial biopsy, guided by a three-dimensional voltage map, showed that myocardial inflammation at histology correlated with a higher prevalence of abnormal bipolar map and greater bipolar low-voltage area extension in patients with BrS [SCN5A variants can be found in patients with arrhythmic myocarditis, even in the absence of the BrS ECG pattern [Lymphocytic myocarditis  with infwith BrS . Notablywith BrS ,58,59. O pattern . These f pattern ,76.SCN5A gene mutation showed histological abnormalities [However, other studies failed to confirm definite myocarditis in biopsies from the RV, by showing only moderate myocardial hypertrophy, moderate fibrosis, and fatty replacement of the myocardium, with hypokinetic RV and RV trabeculae . A genetmalities , and up malities .Epicardial surface and interstitial fibrosis were described in BrS, along with increased collagen throughout the heart and a reduction in the expression of gap junctions in the RVOT. There was a correlation between structural abnormalities and abnormal potentials, and their ablation abolished the BrS phenotype and malignant arrhythmias . AnotherElectroanatomical mapping (EAM) is an invasive method to visualize intracardiac electrical activation . Low vol2 of the abnormal electrophysiological substrate on EAM was described as an independent predictor of inducible ventricular arrhythmias (VT/VF) during programmed ventricular stimulation [In their landmark paper, Nademanee et al. were the first group that performed endocardial and epicardial mapping of the RVOT in a case series of nine patients with a type 1 BrS ECG pattern. They demonstrated that the underlying mechanism is delayed depolarization over the anterior aspect of the RVOT epicardium . The issmulation . Radiofrmulation . In the mulation , cathetemulation  and towamulation . In a symulation .The identification of high-risk BrS patients remains a pivotal issue for the prevention of sudden cardiac death (SCD). Although almost every author agrees on the importance of symptoms and a spontaneous type 1 pattern ,4, some p = 0.049) [A spontaneous type 1 BrS pattern is consistently associated with a higher event rate, even when asymptomatic  . However= 0.049) ,94, a st= 0.049) .Considering the high psychological and physical impact of an ICD in a young population, in the last two decades, other features have been proposed for better stratification of the arrhythmic risk in BrS. So far, little evidence corroborates the hypothesis of a strong association between a specific gene mutation and a worse prognosis . TherefoAmong the clinical parameters, age and the number of familial cases of SCD can help to define the individual risk ,97. AlthAs for the electrocardiographic parameters, QRS fragmentation and duration , late poAlbeit controversial, the prognostic value of VF/VT induction during the electrophysiological test (EPS) remains a cornerstone in clinical practice. The latest ESC guidelines  assign aAn overview of the prognostic factors for BrS is provided in In this setting, the identification of novel prognostic signs from concealed structural abnormalities may considerably improve the patient selection for ICD implants, especially with a primary prevention indication.We hereby showed that BrS sometimes displays concealed substrates that may be identified via advanced diagnostic techniques, including CMR, EMB, and EAM. In this setting, diagnostic criteria for cardiomyopathy may be met more frequently than expected following genetics and simple tests such as ECGs. Waiting for further research and big data analysis, many parameters derived from advanced myocardial imaging, electroanatomical mapping, and histology may be included in a multimodal score to significantly improve the arrhythmic risk stratification of BrS. For instance, LGE , replace


In this novel workup for the diagnosis of the entire spectrum of phenotypic variants of ACM, including left ventricular (LV) variants, cardiac magnetic resonance (CMR) has emerged as the cardiac imaging technique of choice, due to its capability of detailed morpho-functional and tissue characterization evaluation of both RV and LV. In this review, the key role of CMR in the diagnosis of ACM is outlined, including the supplemental value for the characterization of the disease variants. An ACM-specific CMR study protocol, as well as strengths and weaknesses of each imaging technique, is also provided.Arrhythmogenic cardiomyopathy (ACM) is a genetically determined heart muscle disease characterized by fibro-fatty myocardial replacement, clinically associated with malignant ventricular arrhythmias and sudden cardiac death. Originally described a disease with a prevalent right ventricular (RV) involvement, subsequently two other phenotypes have been recognized, such as the • Arrhythmogenic cardiomyopathy includes three different phenotypes: dominant right, biventricular, and dominant left.• In 2020, diagnostic criteria have been updated and cardiac magnetic resonance has emerged as the cardiac imaging technique of choice.• This aim of this review is to provide an update of the current state of art regarding the use of CMR in ACM, with a particular focus on novel diagnostic criteria, CMR protocols, and prognostic significance of CMR findings in ACM. Arrhythmogenic cardiomyopathy is a genetically determined heart muscle disease characterized by fibro-fatty myocardial replacement, clinically associated with malignant ventricular arrhythmias (VAs) and sudden cardiac death .right ventricular dysplasia, because of an abnormal development of right ventricular (RV) musculature, which was observed to be partially or completely substituted by fibro-fatty tissue [dysplasia in favor of cardiomyopathy, in order to emphasize the crucial genetic contribute to the development of the disease [Originally described in 1982 as y tissue , subsequ disease . In fact disease , predisp disease .arrhythmogenic right ventricular cardiomyopathy (ARVC), in which RV morpho-functional abnormalities were predominant, two other phenotypes have been observed: the left dominant variant characterized by a predominant left ventricular (LV) involvement with no or minimal RV abnormalities, and the biventricular variant characterized by a parallel involvement of both ventricles [arrhythmogenic cardiomyopathy (ACM) reflects better the concept of a genetic heart muscle disease, characterized by regional contraction abnormalities and fibrofatty myocardial replacement of one or both ventricles.Although the first described phenotype was characterized by a massive RV involvement, well known as ntricles , 8. For An accurate analysis of ventricular morphology and function is essential for the evaluation of patients and screening of relatives. Imaging techniques mostly used for ACM diagnosis include echocardiography and cardiac magnetic resonance (CMR). Echocardiography is the first imaging tool for the evaluation of patients with suspected ACM, but it has significant limitations in the assessment of RV and is not capable of myocardial tissue characterization. For these reasons, CMR has emerged as the imaging technique of choice in ACM, since it enables detailed morpho-functional and tissue characterization evaluation of both RV and LV.Although the suspicion of ACM has become nowadays a frequent indication for CMR, which is very commonly prescribed in young individuals with cardiovascular symptoms, or electrocardiogram (ECG) abnormalities or premature ventricular beats, CMR laboratories familiar with ACM are limited and gaining experience with it can be hard due to the low prevalence of the disease. A basic understanding of the pathogenesis of ACM combined with the knowledge of technical principles of CMR is required for a reliable study execution and reporting. Incomplete protocols and incorrect interpretations of CMR images, leading to either false negative or false positive results, can have serious consequences for both patients and their families. With this review, we aimed to provide an update of the current state of art regarding the use of CMR in ACM, with a particular focus on novel diagnostic criteria, CMR protocols, and prognostic significance of CMR findings in ACM.The diagnosis of ACM is multiparametric, thus relying on multiple pathologic findings detected by different diagnostic modalities. Since 1994  and thenSince the beginning, the role of CMR in the diagnosis of ACM has been recognized in the clinical demonstration of morpho-functional abnormalities caused by or reflecting the underlying histological changes of RV. In the first International Task Force (ITF) criteria of 1994, imaging criteria were mostly based on RV qualitative assessment and CMR was mentioned among the imaging modalities  for the in vivo evaluation, despite the limited data and experience in this field . Thus, t2 in men and 100 mL/m2 in women) were derived from 462 healthy volunteers of the multi-ethnic study of atherosclerosis, scanned with the traditional fast gradient echo cine sequences [After the inclusion of quantitative metrics in the structural criteria, CMR has gained importance in ACM evaluation, given its recognized high accuracy and reproducibility in chamber volume assessment  and greaequences . Also, tequences , 20. Thiequences . Fourth,equences , was notAll these limitations were reported in a critical review provided by an International Expert consensus document in 2020, in which the clinical performance of the available diagnostic criteria for ACM was investigated and potential areas of improvement were identified, like the absence of specific criteria for left-sided ACM variants and the lack of tissue characterization findings by CMR . The recThe main novelty in the 2020 diagnostic criteria was the acknowledgement that pathogenic mutations, ECG abnormalities, or VAs are no longer sufficient for diagnosis of ACM, but at least one morpho-functional or structural RV or LV criterion, either major or minor, must be demonstrated for diagnosis of each phenotypic variant of ACM. This is a significant change of approach to the diagnosis of ACM, which now, like other structural heart muscle diseases such as hypertrophic and dilated cardiomyopathy, requires the demonstration of structural cardiac abnormalities, thus enhancing the role of cardiac imaging modalities. All modifications included in the 2020 diagnostic criteria concerning the use of CMR, and the rationale behind them are presented in Table PKP2, DSP, DSG2, DSC2, JUP, TMEM43, PLN, DES) were recently identified in an international consensus [These new criteria are heavily dependent on CMR, which has become necessary  for diagnosis of ACM and characterization of disease phenotype, in particular those with LV involvement. In a recent CMR study, we characterized the ACM LV phenotype, pointing out its association with a large amount of non-ischemic LGE, affecting the subepicardial  layers of the LV free wall, mostly the inferolateral region, with or without LV systolic dysfunction . In someonsensus .To demonstrate how the 2020 Padua Criteria may offer the potential to change diagnostic end points and support the goal of improved health care, preliminary data of a comparative diagnostic analysis of a clinical ACM series using the 2010 vs. the new proposed criteria have been recently published . These dDue to the multiple roles of CMR in diagnosis and prognosis of ACM patients, it is crucial to identify the more appropriate study protocol, personalized for each patient on the basis of family history, genotype, and clinical suspicion.CMR study protocol for patients with suspected ACM should include cine sequences for LV and RV, black-blood, flow, and LGE images. The order of sequences and timing in relation to contrast administration can be modified according to laboratories preferences. Number of slices for technique must take in account the patient pre-test probability to have the disease, heart rate, rhythm, and capacity to maintain long and frequent breath-holds. Patients with two among ECG, echocardiography, arrhythmias or family criteria carry a high pre-test probability and deserve a longer and more accurate scan. In Table accordion sign, namely a contraction pattern of RV free wall, found more frequently in asymptomatic first-degree relatives of patients with ACM [butterfly apex, i.e., anatomic variation of the heart, which seems to have two separate apices [The bSSFP sequences are characterized by a good contrast between endocardial borders and blood cavity, allowing a precise estimate of wall thickness, kinetics, biventricular volumes, and function. They have a central role in ACM evaluation, since they allow accurate wall motion assessment of RV and LV, in a reproducible and operator-independent manner. In Table with ACM , and thee apices . DespiteFeature-tracking CMR represents a promising tool for myocardial deformation analysis. In ACM patients, it may permit early diagnosis by detecting subtle wall motion abnormalities, in the absence of macroscopic dysfunction, especially in healthy gene carriers. Lastly, cine images can enable a first assessment of myocardial fat infiltration, in particular in LV variants .bite-like pattern, with regional overlap with LGE lesions [The T1- or proton density–weighted images are useful to identify fatty infiltration, visible as hyperintense signal in comparison to intermediate signal of normal myocardium. The research of myocardial fatty infiltration is motivated by the pathogenesis of the disease, which recognizes in the fibro-fatty lesion its pathologic hallmark , 8 bite-likeper se neither a sign of disease nor a sign of ACM [Nevertheless, the presence of myocardial fat is n of ACM , 36. Myon of ACM –39. Physn of ACM . In an an of ACM . Fatty in of ACM , or can n of ACM , dilatedn of ACM , neuromun of ACM , lipomasn of ACM . In patin of ACM . It genen of ACM . T1 mappAs a general rule, the evaluation of fat infiltration should be subordinated to morpho-functional assessment and scar analysis on cine and LGE CMR, respectively. The presence of myocardial fat should be used as a confirmation of diagnosis, rather than a criterion for diagnosis. Other techniques like the ECG-gated Dixon water-fat CMR are under investigation and appear promising in a more accurate visualization of fat infiltration .hot-phases, an uncommon clinical presentation of ACM occurring more commonly in pediatric patients and carriers of desmoplakin gene mutations, characterized by chest pain and troponin release [The T2-weighted images are commonly used to depict myocardial edema in acute injuries of the myocardium. In patients with ACM, their routine use is not recommended, not for lower importance, but rather for shortening the scan time which would be too long, otherwise. They are, however, highly recommended in ACM patients presenting with  release , 51. In  release , 7 out oT2 mapping is another technique useful for the study of acute myocardial injuries, given a high sensitivity for edema and inflammation. Chun et al recently investigated the application of T2 mapping in ACM patients, and demonstrated an association of high T2 values and heart-failure events  during follow-up .Through-plane motion-encoded phase-sensitive spoiled gradient echo is a useful CMR technique to assess blood flow. In cardiology, they have an indication in valve regurgitation assessment, ventricular output, cardiac shunt, and Qp/Qs estimate. Flow CMR is optional in patients with ACM; however, in the presence of RV dilatation, it is highly recommended to exclude congenital heart diseases, having left-to-right shunt causing RV volume overload, like interatrial septal defects, anomalous pulmonary venous drainages Fig. , or pateEight to 10 min after the gadolinium-based contrast agent administration, phase-sensitive inversion recovery gradient echo sequences permit the visualization, if present, of LGE, such as necrotic or fibrotic myocardium areas which assume a bright signal (hyperenhancement), compared to the remote  myocardium, which remains dark. The pattern of LGE is useful to differentiate post-infarction necrosis  from fibrosis in non-ischemic cardiomyopathies , or myocarditis .all that glitters is not gold and LGE assessment in ACM needs some caveat. Literature data indicate that in RV diseases, LGE has a variable sensitivity, being appreciable in about 30–70% of patients, with possible mismatch when compared to electroanatomic-voltage mapping or endomyocardial biopsy findings [In ACM patients, LGE technique permits the visualization of the hallmark lesions of ACM, which consist of ventricular fibro(-fatty) myocardial replacement. Furthermore, it can help categorize the ACM phenotypic variant , and risfindings –57  quantification are useful imaging techniques able to identify an increase of interstitial space, due to diffuse fibrosis or infiltration, particularly helpful in the differential diagnosis of cardiomyopathies with hypertrophic phenotype . AlthougIt has been also proposed that T1 changes may precede LV focal abnormalities in ACM and favor early diagnosis. Georgiopoulos et al indeed demonstrated an abnormal increase of T1 values in 11/30 ACM patients (37%), including those with normal LV at conventional imaging tests .Besides the diagnostic purposes, CMR findings can also help risk stratify ACM patients for arrhythmic events and guide life-saving therapy as implantable cardioverter-defibrillator (ICD) implantation. In the 2015 International Tack Force paper, severe RV dilatation and dysfunction are considered among the strongest predictors of malignant arrhythmias and therefore primary prevention ICD implantation is recommended in these patients regardless of arrhythmic burden . FurtherThe traditional classification of cardiomyopathies relied on traditional diagnostic techniques like echocardiography and angiography, able to identify morpho-functional anomalies of the heart like hypertrophy, dilatation, and restriction. However, in the last decades, it is emerging that information coming from CMR myocardial tissue characterization  are crucial for a better understanding of cardiomyopathies and for improvement of diagnostic accuracy and risk stratification. In particular, CMR shed light upon ACM, because it allowed to characterize the disease phenotype, particularly the biventricular and left-dominant ones, to exclude phenocopies and risk stratify patients. The Padua Criteria underscore the increasing clinical experience with the expanding spectrum of ACM phenotypes and aim to improve the diagnosis of ACM, particularly by means of CMR. Like previous ITF criteria, also the Padua Criteria need to be further validated by clinical studies in large cohorts of “real word” patients.


Recurrent falls are a concerning problem in the elderly. Elderly people aged > 65 years who are prone to fall often require medical treatment for severe fall-related injuries, which is associated with a substantial financial burden. Therefore, this study aimed to identify factors related to recurrent falls in the community-dwelling young-old (65–74 years old) and old-old (≥ 75 years) in South Korea.This study used a cross-sectional, correlation design. Data from the 2017 National Survey of Older Koreans were used, and 5,838 young-old and 4,205 old-old elderly people were included in the analysis. The questionnaire included general characteristics, fall experience, physical status, mental status, and presence of chronic diseases. The data were analyzed using the chi-square test, one-way analysis of variance, and logistic regression analysis.p < .001), use of visual aids (p = .002), cognitive function (p < .001), presence of suicidal ideations (p = .005), number of chronic diseases (p < .001), and number of prescribed medications used (p = .006) associated with fall recurrence. In the old-old elderly people, having a spouse (p = .034), being a beneficiary of the National Basic Livelihood Security System (p = .025), less exercise (p = .003), limitations in activities of daily living (p < .001), visual aid use (p = .002), presence of suicidal ideations (p = .015), number of chronic diseases (p < .001), and presence of Parkinson's disease (p < .001) associated with fall recurrence.In the young-old elderly people, limitations in activities of daily living (This study identified differences in factors related to fall recurrence between the young-old and old-old elderly. The results of this study indicate that it is necessary to implement an intervention program to prevent fall recurrence by age group in consideration of the risk factors for fall recurrence in each elderly people group.The online version contains supplementary material available at 10.1186/s12877-022-03172-7. In Korea, 15.7% of the total population of 8,125,000 people is older than 65 years and because Korea is a super-aged society, this proportion is expected to increase to 20.3% by 2025 . In partTo prevent falls, studies have evaluated various related predictive factors. The risk factors for falls that have been reported in different studies include age , sex 6]6], incomFalls may occur repeatedly in individuals. In fact, 50% of elderly people population have experienced recurrent falls . Those wIn studies on the elderly, individuals with age differences of 20–30 years have been grouped together for comprehensive assessment; however, such a classification may overlook the differences in health conditions and the problems of the young-old (65–74 years old) and old-old (≥ 75 years). . TherefoTo predict and prevent fall recurrence in the elderly, we must understand the risk factors for recurrent falls and identify the predictive factors of falls with detailed standards that consider the characteristics of elderly people by age group. Therefore, this study assessed the predictive factors of fall recurrence in the young-old and old-old elderly people.This cross-sectional study aimed to identify the factors that are related to recurrent falls in the young-old and old-old elderly. This study used raw data from the 2017 National Survey of Older Koreans that was conducted by the Korea Institute for Health and Social Affairs using interviews of individuals aged over 65 years living in community. Random sampling was performed by stratifying the population, and subjects living in special care facilities were excluded. Among the 10,299 participants aged over 65 years, those with missing values in related measured items were excluded, and 5,838 and 4,205 young-old and old-old elderly people were analyzed in this study.The item “Have you experienced falls  in the past year? If yes, how many times?” was used to assess fall experience and was answered as yes, no, and the number of times, if any.Sex, education level, having a spouse, National Basic Livelihood Security System (NBLSS) beneficiaries, smoking habit, problematic drinking, and exercise were assessed. The NBLSS is a government-supported benefit to guarantee minimum living and is indicative of poverty. The current smoking status was evaluated, and problematic drinking was defined as the consumption of more than three drinks daily in the last month. Exercise was assessed based on the responses “yes” or “no” to exercising more than once a week for 10 min or more each time.Factors including limitations in activities of daily living (ADL) and instrumental activities of daily living (IADL), visual aids, and body mass index (BMI) were measured to evaluate the participants’ physical status. ADL were measured using the Korean version of the daily life activity measurement tool . FurtherMental status including depression and suicidal ideation were measured by self-report questionnaire. Depression was assessed based on whether the participants experienced depression for more than 3 months, and suicidal ideation was assessed based on the answers to the item “Have you ever considered committing a suicide after the age of 60?” (yes or no).The chronic disease characteristics were assessed according to cognitive function of the participants and the number of chronic diseases present for more than 3 months (according to the doctor's diagnosis). The cognitive function was measured using the Korean Version of the Mini Mental Status Examination for Dementia Screening (MMSE-DS) . The MMSStatistical analyses were performed using IBM SPSS 25.0. The participants’ general characteristics, physical and mental states, and chronic disease characteristics are presented as frequency, percentage, mean, and standard deviation. The differences in fall frequency were analyzed according to the participants’ general characteristics, physical and mental states, and chronic disease characteristics using the chi-square test, one-way analysis of variance, and Scheffe test for post-hoc comparisons. The factors affecting recurrent falls were analyzed using a logistic regression analysis.Single falls occurred in 516 (8.8%) and 516 (12.3%) participants in the young-old and old-old groups, respectively, whereas recurrent falls occurred in 263 (4.5%) and 283 (6.7%) participants, respectively.In the young-old group, recurrent falls rates were significantly associated with females, those with education level below elementary school, those with no spouse, those who were NBLSS beneficiaries, those who did not smoke, those who were not problematic drinkers, and those who exercised. In the old-old group, recurrent falls rates were significantly associated with females, those who had no spouse, those who were NBLSS beneficiaries, and those who did not exercise Table .Table 1DIn the young-old group, recurrent falls rates were significantly associated with limitations in ADL or IADL, used visual aids, had a high BMI, had depression, and had suicidal ideation. In the old-old group, recurrent falls rates were significantly associated with limitations in ADL or IADL, used visual aids, had depression, and had suicidal ideation Table .Table 2DIn both groups, recurrent falls rates were significantly associated with an impaired cognitive function, with higher number of chronic diseases, and higher number of prescribed medications. In the young-old group, recurrent falls rates were significantly associated with hypertension, stroke, angina and myocardial infarction, diabetes, arthritis, osteoporosis, lumbodynia, sciatic neuralgia, cataract, glaucoma, chronic kidney diseases, urinary incontinence, anemia, insomnia, and Parkinson’s disease. In the old-old group, recurrent falls rates were significantly associated with hypertension, arthritis, osteoporosis, lumbodynia, sciatic neuralgia, glaucoma, urinary incontinence, anemia, dementia, insomnia, and Parkinson’s disease Table .Table 3DThe Hosmer–Lemeshow test showed that the fitness of the extracted models for the young-old and old-old elderly people was 0.77 and 0.32, respectively, indicating that the estimated models had a statistically good fit.In the young-old group, those with limitations in ADL and who used visual aids were 2.25 and 1.56 times more likely to experience recurrent falls than those without such limitations. When the cognitive function score increased by one point, the odds of recurrent falls increased by 0.93 times. Those with suicidal ideations experienced recurrent falls 1.69 times more than those without suicidal ideations. As the number of chronic diseases and prescribed medications increased by one, the odds of recurrent falls increased by 1.22 and 1.06 times Table .Table 4FIn the old-old group, those who had no spouse, were NBLSS beneficiaries, did not exercise, had limitations in ADL, used visual aids, and had suicidal ideation were 0.76, 1.53, 0.68, 1.98, 1.54, and 1.63 times more likely to experience recurrent falls. As the number of chronic diseases increased by one, the odds of recurrent falls increased by 1.18 times, and those with Parkinson's disease had a 3.53 times increase in the odds of recurrent falls (Table This study assessed the predictive factors of recurrent falls by age group in the young-old and old-old elderly. Both single and recurrent fall rates were higher in the old-old elderly, which is consistent with the results of a previous study that reported an increased rate of falls with age . AdditioThe predictive factors of a high recurrence rate of falls were determined by focusing on the commonalities and differences between elderly people groups. In both young-old and old-old groups, factors that affected recurrent falls were limitations in ADL, use of visual aids, presence of suicidal ideations, and a number of chronic diseases. The young-old and old-old elderly people with limitations in ADL were more likely to experience recurrent falls, which is consistent with the results of a previous study  that shoThe young-old and old-old elderly people who use visual aids may experience more recurrent falls than those who do not use visual aids. Visual aids are required in those with a decreased visual function, and our finding on the relationship between the use of visual aids and falls are consistent with the findings of studies showing that sensory deficits such as vision and hearing impairments may be closely related to falls –21. The The young-old and old-old elderly people with suicidal ideations experienced recurrent falls more frequently than those without. Considering the close relationship between depression and suicidal thoughts, this finding was partially consistent with that of a study that showed a strong relationship between depression and falls . In a stIn our study, as the number of chronic diseases increased by one, the young-old and old-old elderly people were more likely to experience recurrent falls. This is consistent with the findings of a study that showed that the number of chronic diseases present was related to falls . In anotThere were some differences in the factors that affected recurrent falls in the young-old and old-old elderly. In the young-old elderly, cognitive function and number of prescribed medications used were predictors of recurrent falls. This is consistent with the finding that decreased cognitive function increased the risk of falls . In the As the number of prescribed medications used increased by one, the odds of recurrent falls increased by 1.06 times, which is consistent with the finding that the use of medication increased the risk of falls in the elderly people . Anti-coUnique predictive factors of recurrent falls in the old-old elderly people were spouse status, being NBLSS beneficiaries, less exercise, and the presence of Parkinson’s disease. As noted in a study reporting that having a spouse was a factor that affected falls , our finFurthermore, NBLSS beneficiaries were 1.53 times more likely to experience recurrent falls, which supported a WHO report that included socioeconomic factors, such as poverty, as risk factors for falls [Those who did not exercise were more likely to experience recurrent falls. This finding is consistent with the results of a previous study that indicated that a lack of exercise was the main risk factor for falls in the elderly people over the age of 80 years . HoweverLastly, those with Parkinson’s disease were more likely to experience recurrent falls than those without, which is consistent with previous results that indicated that Parkinson’s disease is closely related to falls because it affects motor function . MoreoveThis study observed differences in factors related to recurrent falls between the young-old and old-old elderly. Risk assessments that reflect the characteristics of different age groups of elderly people must be developed to screen for recurrent falls in the community. Additionally, further studies that evaluate the effects of interventions and strategies that can prevent recurrent falls in high-risk groups are required.The cross-sectional design of this study limited the assessment of causality of the relationship between the variables. It is recommended that longitudinal studies that include causal variables to assess the cause-and-effect relationship should be conducted in the future. Furthermore, fall experience and related factors were assessed using a self-reported questionnaire. Therefore, it would be necessary to perform objective measurement in future studies to compare with the results of subjective questionnaires.This study found that there is a difference in the factors related to recurrent falls between the young-old and old-old elderly. The results of this study indicate that it is necessary to implement an intervention program to prevent fall recurrence by age group in consideration of the risk factors for fall recurrence in each elderly people group.Additional file 1. 2017 National Survey of Older Koreans_FALL.


Valve leaflets and chordae structurally normal characterize functional mitral regurgitation (FMR), which in heart failure (HF) setting results from an imbalance between closing and tethering forces secondary to alterations in the left ventricle (LV) and left atrium geometry. In this context, FMR impacts the quality of life and increases mortality. Despite multiple medical and surgical attempts to treat FMR, to date, there is no univocal treatment for many patients. The pathophysiology of FMR is highly complex and involves several underlying mechanisms. Left ventricle dyssynchrony may contribute to FMR onset and worsening and represents an important target for FMR management. In this article, we discuss the mechanisms of FMR and review the potential therapeutic role of CRT, providing a comprehensive review of the available data coming from clinical studies and trials. Functional mitral regurgitation (FMR) is a pathological condition in which the mitral valve is structurally normal, and the disease results from valve deformation caused by left ventricular (LV) dysfunction and remodeling . It can FMR results from multiple factors: decreased contractility, ventricular remodeling, impairment of mitral annular function, and ventricular dyssynchrony. Additionally, FMR tends to progress over time due to chronic volume overload, according to the classical motto “mitral regurgitation begets mitral regurgitation” . The vicThe present review will focus on the clinical impact of CRT on FMR, examining data regarding post-procedure and long-term outcomes of CRT in patients with FMR. Furthermore, we aim to provide the rationale for using mitral percutaneous interventions in patients in which FMR improvement is not achieved with CRT. The main determinants of FMR are the complex and heterogeneous changes in the MV apparatus that may occur in HF. Normally, the MV leaflets close in a coaptation point within the annular plane and have a considerable overlap when they face one to the other (coaptation reserve). In FMR, the coaptation reserve is progressively reduced until coaptation is no more possible. The main determinant of the reduction of coaptation reserve is the predominance of tethering forces: LV remodeling and dilation cause papillary muscles (PMs) dislocation away from the mitral annulus . ConsequThis imbalance between the two opposing forces generates a typical phasic intra-beat variation in the time course of the regurgitant orifice area in FMR, known as the ‘loitering pattern.’ The orifice area and regurgitation are greater in early and late systole and lower in the mid systole when the higher peak LV pressure facilitates valve closure.Beyond intra-beat variability, FMR severity may also have a beat-to-beat variation. This characteristic depends on the phasic changes in the balance between tethering and closing forces and on the physiologic and/or pharmacologic factors able to modify this equilibrium. Exercise contributes to a greater cardiac load and may also trigger dynamic geometric changes in the LV and mitral valve apparatus, thus causing MR worsening  Figure . In partThe geometrical distortions of the mitral annulus caused by LV dilatation contribute to FMR ,21. The Another contributing factor that may worsen FMR in patients with HF is mitral annular enlargement driven by left atrial dilatation in the presence of atrial fibrillation . This meLastly, different studies suggest an organic contribution to functional mitral regurgitation. It was shown that loading conditions in patients with HF result in structural and biochemical alterations in MV leaflets, characterized by a significant increase of glycosaminoglycans and collagen. Moreover, it was reported that these valves in HF have greater concentrations of cells and a lower concentration of water. In turn, the greater concentration of cells indicates an upregulation of mitogenic activity, resulting in increased matrix synthesis. The loss of water, which is a major component of the extracellular matrix and contributes to tissue viscoelasticity, is likely responsible for reduced viscous relaxation. Therefore, these compositional alterations observed could have functional consequences on the valves resulting in stiffer, less extensible, and less viscous ,30,31,32LV mechanical dyssynchrony could be a potential contributing factor to FMR by several mechanisms. First, the mechanical dyssynchrony of LV segments increases the tethering force in dual modes: displacement of PMs with consequent lack of leaflets coaptation and uncoordinated regional mechanical activation due to dyssynchrony both contribute in distorted MV apparatus geometry . MoreoveAccording to guidelines for managing HF, optimal medical therapy should be the first step in managing all patients with FMR . CRT shoMany studies have shown that CRT reduces FMR by increasing closing forces and, more importantly reducing tethering forces through “local” synchronization. Indeed, CRT acutely determines resynchronization of the PMs, leading to a shortening of MR duration and later onset of MR ,44.Other potential contributions of CRT may derive from reshaping annular geometry and function and decreasing sphericity indices ,46. ThisCRT has also been associated with left atrial reverse remodeling and a decrease in the burden of atrial fibrillation, which is implicated in mitral annular dilatation in patients with HF .Regarding the long-term effects of CRT on FMR, they are mainly represented by the increase of closing forces and the global LV inverse remodeling. These results have been achieved after 3–6 months of CRT on top of optimized medical treatment and are even more evident during longer follow up .In conclusion, immediate FMR reduction after CRT implantation is the expression of balancing of tethering and closing forces and results from an acute reduction in volume overload. The immediate FMR reduction also favors reverse remodeling and has been demonstrated to be a robust prognostic determinant after CRT. In the long-term, FMR reduction is the expression of LV healing and reverse remodeling .In a post hoc analysis of the Cardiac Resynchronization—Heart Failure trial (CARE-HF), patients assigned to CRT were more likely to have an improvement in MR and a reduction in NT-proBNP after three months of follow-up. This finding suggests that this factor may predict or mediate some of the long-term response to CRT. The baseline degree of MR was not reported .Previous studies  reported at least the FMR grade before and after CRT implantation and demonstrated a small but significant reduction in FMR severity at 3–6 months. In the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial, MR decreased significantly at three and six months in patients with moderate-to-severe HF who received CRT . Linde Cp = 0.016). These results suggest that CRT at least stabilizes and does not worsen FMR.It is important to underline that in these early 2000s trials, MR evaluation was limited by heterogeneity in the definition of its mechanism and the methods of quantification. Indeed, regarding the methods of MR quantification, MR jet area and MR jet area/LA area were often used. However, both these methods may be subject to errors: in many cases, the regurgitant jet is eccentric due to asymmetric tenting of the posterior leaflet, and consequently, the size and width of the color jet may be underestimated. Moreover, while the first studies and landmark trials on CRT were not specifically evaluated to address the reduction of FMR after biventricular pacing, and only qualitative MR assessment was described, the latest studies provided a quantitative and more detailed assessment of MR . In a poThe persistence of FMR is associated with worse outcomes, as demonstrated by an observational study by Cabrera Bueno et al. This study included 32 patients (42%) with baseline moderate or severe FMR. However, in most of the study population (65.7%), FMR remained unchanged or worsened .On the other hand, Verheart et al., in a retrospective observational study, reported that patients with significant FMR pre-CRT experienced more reverse remodeling, indicating that severe FMR does not interfere with the effects of CRT . All patPatients with moderate to severe FMR have been so far underrepresented in clinical studies. Therefore, Van Bommel and colleagues exclusively included patients with grade three and four FMR (according to ACC/AHA guidelines) and high operative risk for MV surgery in a prospective study ,55. It wIf FMR persistence in CRT patients is associated with a worse outcome, it is crucial to proceed to FMR correction in non-responders and, therefore, to establish the optimal timing for FMR correction. Regarding this issue, useful information was provided by a multicentre retrospective study by Di Biase L et al. MR severity and LV reverse remodeling at baseline and at three and twelve months after CRT implantation were assessed . AdvanceIn conclusion, data from clinical studies and trials suggest that it is possible to achieve MR improvement early after CRT implantation, but more commonly after three or six months and more often in sinus rhythm patients. Sometimes CRT neither modifies nor worsens MR, but this is associated with an unfavorable long-term survival.In 20–25% of CRT patients, significant MR persists. These numbers concern patients with grade ≥2 FMR and are often found to be CRT non-responders. It is unclear why these patients do not benefit from CRT compared to their counterparts. In ischemic patients, significant scar burden may hamper the benefits of CRT on FMR. Different studies suggest that patients with baseline greater ventricular volumes and greater EROA, i.e., greater severity of FMR, experienced less reverse remodeling than patients without FMR at baseline. Therefore, globally available data support the idea that maximum benefit in CRT is obtained in patients ill enough to get improvement but not too ill to be able to get any benefit.Catheter-based treatment with the MitraClip  and, more recently, PASCAL clip  have been proposed as an additional therapeutic option in selected patients with FMR ,58. Due So far, two randomized studies have been published focusing on subjects with FMR: the MITRA FR trial and the COAPT trial. In the French study MITRA FR, 307 patients with HF and severe FMR were randomly assigned to edge-to-edge mitral valve repair plus optimal medical treatment or optimal medical treatment alone . Prior CMany reasons have been suggested to justify this discrepancy in outcomes between the trials. 2), showing that these patients are unlikely to benefit from transcatheter mitral valve repair. This finding is in line with post hoc subgroup analysis of COAPT, demonstrating that patients with EROA ≤ 30 mm2 and left ventricular end-diastolic volume > 96 mL/m2 (10.2% of the COAPT study population) demonstrated no change in all-cause mortality or heart failure re-hospitalization one year after MC implantation. Therefore, the differences in outcomes between these two trials suggest that patient selection is critical for reaching procedural clinical success. Additionally, returning to resynchronization therapy, it can probably be said that even for CRT the key aspect is represented by patient selection. However, the identikit of the perfect candidate (responder) for CRT, is not yet well established.The main difference was in patient selection: the COAPT trial included patients with moderate left ventricular dilatation and more severe MR. Conversely, the MITRA-FR trial included patients with extreme left ventricular dilatation and less severe FMR  therapy could be considered as a bridge to transplantation and/or destination therapy. It has been reported that mechanical unloading with LVAD leads to a reduction in the severity of FMR in these patients. However, in this case, moderate or severe FMR persists in nearly 20%–30% of patients. Risk factors for residual FMR include younger age, female gender, non-ischemic heart failure etiology, and pre-implant right ventricular dysfunction. Residual MR is associated with an increased risk of right heart failure and renal failure and a trend toward mortality on LVAD support.Firstly, it is important to use the same language: there is a need to standardize the methodology to assess the severity of FMR. Being a dynamic lesion is a feature of FMR in patients with HF; accordingly, its severity may vary over time. FMR is also very sensitive to loading conditions, and many patients with HF use drugs that modify preload. Therefore, using the traditional color Doppler flow mapping in the left atrium and measuring the regurgitant jet width to quantify FMR may lead to errors. The quantitative method using the Doppler measurement of stroke volumes or, when feasible, the analysis of the flow convergence zone using the PISA method is more accurate. It has been shown that the regurgitant volume and, specifically, the EROA are less load-dependent and more reliable. In moderate MR, exercise echocardiography may be useful for quantifying exercise-induced changes in mitral regurgitation .In this context, an important unresolved issue is understanding when patients are truly refractory to medical therapy. The severity of FMR should be reassessed after optimized medical treatmDent. The latest AHA/ACC valve guidelines suggest the supervision of a cardiologist expert in the treatment of patients with HF to achieve optimal results and to determine with the multidisciplinary team when symptoms are truly refractory to guideline-directed medical therapy before decisions are made for further treatments. In addition, it is important that medical therapy should be up-titrated to the maximum tolerated dose to achieve the greatest possible benefit.LV ejection fraction should be carefully addressed when significant FMR is concomitantly present. For this reason, proper LV function assessment plays a central role and may influence the timing for CRT therapy, which might affect the CRT response. Indeed, LV ejection fraction overestimation in patients with severe FMR in some cases might exclude patients from the CRT indication and, consequently, prolong the timing for intervention. Moreover, following the HF treatment flow chart as proposed by European guidelines, those patients treated with Sacubitril/Valsartan might improve their LV function, preventing CRT implantation. However, some of them might already have or develop dyssynchrony without being suitable candidates for CRT due to LVEF >35% under Sacubitril/Valsartan effects.A second aspect concerns mechanical dyssynchrony in the absence of electrical dyssynchrony. Data showing LV dyssynchrony in patients with HF and narrow QRS or effectiveness of CRT in non-LBBB ECG suggest that further randomized studies are needed and, possibly, CRT indications updated. Indeed, echocardiography and its advanced tools  allow the detection of mechanical dyssynchrony in those cases where electrical dyssynchrony is absent and, consequently, they might play a role in the future as adjunctive techniques for best patient selection and CRT optimization.The maximum benefit of CRT on FMR and LV remodeling should be observed in those patients with at least mild MR, not reaching a severe degree, which may represent a too late and perhaps irreversible stage of LV dysfunction and dilatation to receive benefit from electrical therapy. However, dyssynchrony is only one component of a highly complex pathology, and consequently, CRT alone has some intrinsic limitations for FMR resolution. Technical improvements in the field of electrophysiology with new leads and algorithms are going to increase the rate of success of such therapy. All the available tools, from medical therapy to MR correction, should be, therefore, considered in order to correctly address FMR and reverse the vicious cycle of HF-FMR. Further investigations are warranted to elucidate the potential benefit of combining CRT with specific therapeutic approaches for the mitral valve in patients with FMR and indications of CRT, like surgical annuloplasty or percutaneous therapies.FMR, in the context of HF, is not an innocent bystander but significantly impacts survival. Consequently, FMR and HF should not be treated as two different pathologies but should be considered a unique, complex syndrome. Therefore, a multilevel approach aiming at addressing all the underlying mechanisms and complications of HF should be preferred. In this perspective, the multidisciplinary Heart Team, with multiple subspecialities, will play a central role to provide the best approach to such a multifaceted and life-threatening condition.


More than 70% of thalassemia’s major mortality is due to the cardiac complications of this syndrome, mostly consequent to myocardial Iron overload; therefore, evaluation of such complications is of utmost importance. T2*MRI is used to assess hepatic and myocardial Iron load in thalassemia patients, which is not always available. Signal-Averaged Electrocardiography is a rather easy method of evaluating major thalassemia patients regarding their risk for sudden cardiac death.In this cross-sectional study, 48 patients with thalassemia major underwent evaluation with electrocardiography, signal-averaged electrocardiography, echocardiography, T2*MRI, and ferritin level. The association of the existence of ventricular late potentials in SAECG and other cardiac variables was evaluated. Moreover, the association between myocardial and hepatic Iron load and cardiac characteristics was assessed.P = 0.011). Nonspecific ST-T changes and premature atrial and ventricular contractions were seen more frequently in patients with late potentials . Patients with higher myocardial and hepatic Iron loads had longer QTc in their 12-lead surface electrocardiograms.48 patients with a mean age of 30.31 ± 7.22 years old entered the study. 27 (56.3%) of the patients had ventricular late potentials, which were associated with myocardial dry Iron weight (Patients with ventricular late potentials assessed by SAECG had a higher myocardial Iron load. Higher myocardial Iron load is associated with higher cardiac complications in patients with beta-thalassemia major; therefore, SAECG can be used as a screening test for cardiac complications in beta-thalassemia major patients. Major beta-thalassemia is an inherited hypoproliferative anemic syndrome characterized by hypochromia, microcytosis, and a substantial decline in β chain synthesis that acts as a major concern in healthcare systems around the world . PatientExcessive Iron overload in cardiac tissues in major beta-thalassemia patients results in various cardiac complications such as dilated cardiomyopathy, arrhythmias, and congestive heart failure . Such caHepatic and cardiac Iron overload in major thalassemia patients can be assessed using imaging modalities such as T2* magnetic resonance imaging (T2*MRI) . T2*MRI The Signal-Averaged electrocardiogram is a rather easy method of evaluating major thalassemia patients regarding their risk for sudden cardiac death . ElectroThis study was conducted in accordance with the Declaration of Helsinki and approved by the Committee of ethics in biomedical research of Shiraz University of Medical sciences by the code IR.SUMS.MED.REC.1400.235. A written consent form was obtained from the patients or their legal guardians.Based on a similar study conducted by Aggarwal et al. considering a type I error of 0.05 and a study power of 80%, using MedCalc Software, the minimal sample size for the study to be statistically significant was 46. The samples were chosen among Major Thalassemia patients referred to the Genetic Research Center of Shahid Dastgheib Hospital affiliated with Shiraz University of Medical Sciences with a random convenience method. The recruitment of the participants lasted from August 2020 to March 2022.The inclusion criteria of our study were 10–45-year-old Major Beta-Thalassemia patients who required repeated blood transfusions and Iron chelators from their childhood. The exclusion criteria of our study were: being afflicted with hypertension, diabetes mellitus, gout, ischemic heart disease, cardiac or vascular anomalies , and history of active cigarette smoking, any present inflammatory symptoms such as rhinorrhea, cough, pharyngitis, fever, and rhinorrhea, any history of inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, the unwillingness of the patients or their legal guardians to participate in the study, and being younger than 10 years old or older than 45 years old.This study followed a descriptive cross-sectional protocol involving 48 MT patients referred to the Genetic Research Center of Shahid Dastgheib Hospital, affiliated with Shiraz University of Medical Sciences. 48 patients with major thalassemia requiring repeated blood transfusions aged between 10–45 years old entered the study. The sampling followed a randomized convenience method.3, and average pre-transfusion hemoglobin level. The fifth part of the checklist was allocated to electrocardiographic findings  in a six-minute ECG. Signal Averaged Electrocardiographic findings  were included in this section.In this study, a checklist was filled out for each patient after obtaining the written consent form from the patients or their legal guardians. The checklist consisted of five sections. First, demographic information such as age, sex, the frequency of packed cell transfusions, the interval between transfusions, the total number of transfused packed cells, and age at the time of first blood transfusion. The second part of the checklist was attributed to the past medical history of the patients, such as the history of diabetes mellitus, hypothyroidism, adrenal insufficiency, and history of splenectomy, as well as drug history . The third section involved the information obtained from echocardiography and cardiac Magnetic Resonance Imaging of the patients, such as left ventricular systolic and diastolic function, cardiac chamber sizes, and iron loading state in T2* mapping of liver and heart besides the dry weight of Iron in the heart and the liver. The fourth section of the checklist included the biochemical lab data of the patients as serum ferritin level , Calcium, 25(OH) Vitamin DSignal‐averaged electrocardiography (SAECG) records low‐amplitude electrical activity in the myocardium. It is used to detect the depolarization of ventricular areas with slow consequences to Iron overload manifested as late potentials (LPs). LPs are described by the duration of the terminal portion of the QRS complex that displays slow amplitude signals  and indirectly by the total duration of the filtered QRS complex. Their magnitude is measured by the root mean square voltage of the terminal 40 ms of the filtered QRS complex (RMS‐40). The criteria for diagnosis of LPs proposed in 1991 include (i) filtered QRS duration ≥ 114 ms, (ii) RMS‐40 < 20 μV, and (iii) LAS‐40 > 38 ms . ImportaAll of the SAECGs were obtained with “late potential ECG” software from Biomedical Systems revision 5. 0. 3 with an HP Filter of 40–250 Hz and an average beat of 250. HF Noise of less than 0.5 microvolts were considered acceptable. Conventional twelve-lead ECG was also obtained from all patients.Cardiovascular Magnetic Resonance (CMR) imaging is used as a noninvasive method to evaluate the amount of iron in the heart. MRI examinations were performed with a 1.5 Tesla (T) Magnetom Avanto scanner . The scans included measurement of the liver R2 value and the myocardial T2* value. The scan duration was 45 min. The T2* of the heart was assessed by a cardiac gated single breath-hold multi-echo technique. T2* analysis was conducted using Thalassemia Tools via CVI42 software from Circle company, Calgary, Canada. A full-thickness region of interest (ROI) was drawn in the mid-interventricular septum. The signal intensity of this region for each echo time was measured and plotted as an exponential signal decay curve. Post-processing of acquired images was done by plotting signal intensities and using the curve fitting technique by the CMR42 workstation.The lower limit of normal for T2* in the detection of myocardial iron deposition has been reported as 20 ms, and this value was used as the cut-off in this study . PatientThe data were entered into IBM SPSS version 22.0 . The qualitative data were reported as frequency and percentages, and the quantitative variables were reported as Mean ± SD. T2* was shown as a geometric mean . Correlations between the myocardial T2* value, liver T2* value, echocardiographic parameters, and the serum ferritin level were assessed by Spearman’s rank test. The parameters observed at different levels of T2* and late potentials were compared using one-way ANOVA . For the comparison of categorical variables, chi-square and Fisher’s exact tests were used, while an independent two-sample T-test was applied for continuous variables. P-values less than 0.05 were considered statistically significant.A total of 48 patients with major thalassemia entered the study. 64.6% (31) of the patients were male, and 35.4% (17) were female. The mean age of the participants was 30.31 ± 7.22 years old. The mean age at which transfusions were initiated was 14.94 ± 15.90 months old. The interval between transfusions varied between 14 to 30 days. The mean number of total transfused packed cells in patients was 1077.08 ± 360.30. the average serum ferritin level of the patients was 4020.94 ± 4132.31 ng/ml ranging from 155 to 15,387 ng/ml.Myocardial and hepatic Iron load were assessed using T2* MRI. In this study, the mean myocardial T2* and hepatic T2* conduction times were 20.29 ± 12.44 and 6.45 ± 6.26 ms, respectively. The findings were equivalent to 2.74 ± 2.55 and 13.99 ± 15.49 mg/g dry Iron weight.In this study, 25 (52.1%) of the patients had a normal myocardial Iron load (T2*MRI > 20 ms), 6 (12.5%) had moderate myocardial Iron overload (T2*MRI 10–20 ms), and 15 (35.4%) had severe myocardial Iron overload (T2*MRI < 10 ms). 10 (20.8%) patients had a normal hepatic Iron load (T2*MRI > 11.4 ms), while 18 (37.5%) had moderate hepatic Iron overload (T2*MRI 3.3–11.3 ms), and 20 (41.7%) had severe hepatic Iron overload (T2*MRI < 3.3 ms).All of the patients underwent cardiac assessment by SAECG, six minutes12-lead surface ECG, and Echocardiography. 27 (56.3%) of the patients had ventricular late potentials in their SAECG. 18 (37.5%) of the patients had filtered QRS duration > 114 ms, 16 (33.3%) of the patients had terminal QRS root means square (RMS) voltage < 20 µV, and 27 (56.3%)of the patients had last amplitude (< 40 µV) signal duration of longer than 38 ms.Table Various abnormalities were found in the electrocardiograms and echocardiograms of the patients. The association between abnormalities such as diastolic dysfunction, premature atrial contractions, and early repolarization, among others, with the existence of Late potentials in the SAECG, are summarized in Table As can be deducted from Tables Cardiac and hepatic Iron overload was investigated using T2*MRI, and the Iron dry weight of both organs was estimated using this method. Patients were divided into three groups regarding their myocardial Iron load and three groups regarding their hepatic Iron load . Various electrocardiographic, SAECG, and echocardiographic findings were compared in these groups, which are summarized in Table c . Ferritin level had a significant correlation with hepatic dry Iron weight  but not myocardial dry Iron weight . among SAECG findings, myocardial dry Iron weight had a significant direct correlation with LAS-40 . moreover, the duration of the filtered QRS wave and P–R interval showed a significant and direct correlation . the results of Pearson’s correlation tests are summarized in Table Pearson’s correlation test was used to assess the relationship between echocardiographic, electrocardiographic, T2*MRI, and SAECG findings. Myocardial and hepatic dry Iron weight had significantly positive correlations with QTc. The application of T2* MRI in defining tissue Iron load in thalassemia patients has long been proven [In this study performed on 48 major thalassemia patients, we found that the mean hepatic and myocardial T2*MRI conduction times were 20.29 ± 12.44 and 6.45 ± 6.26 ms, respectively. Patients with ventricular late potentials in their SAECG tended to have lower myocardial T2*MRI conduction times and, thus, have higher myocardial Iron loads. Patients with ventricular late potentials in their SAECG also had higher rates of non-specific ST-T changes, Premature atrial contraction, and Premature ventricular contractions. Moreover, patients with higher myocardial and hepatic Iron load had longer QTn proven , 14. TheDaar et al. have found that lower cardiac T2* in thalassemia major patients is associated with higher mortality; consequently, further evaluation of patients with lower cardiac T2* is of great importance . MoreoveIn our study, although ferritin level was associated with hepatic Iron load, it did not have any association with the cardiac Iron load. This finding was in line with the findings of a study performed by Khadivi Heris et al. on 58 thalassemia major patients . They alIn a study by Dursun et al., the authors found that lower cardiac T2* MRI conduction time was associated with a larger interventricular septum and higher left ventricular mass, which can be due to iron deposition in the cardiac tissue . Howeverc in the patients [In a study by Aggarwal and colleagues performed on 48 thalassemia major patients, higher cardiac Iron overload was associated with longer QTpatients . This fiIn a study by Hayıroğlu et al., they used a formula devised from 12-lead ECG findings to predict the existence of diastolic dysfunction in patients. Such findings can also be extremely useful in the population of patients with major thalassemia since most of the patients with cardiac Iron overload have diastolic dysfunction, which might end in further complications such as heart failure with preserved ejection fraction and ultimately sudden cardiac death .c, did not differ in patients with and without ventricular late potentials. This might indicate that ventricular late potentials have higher sensitivity and lower specificity for cardiac abnormalities such as QT prolongation; therefore, this method can be used as a screening tool for cardiac complications of beta thalassemia major.In this study, we also assessed the patients using signal-averaged electrocardiography since T2* MRI is not always available, but recording SAECG is a rather easy way of ventricular function assessment. In our study, patients with ventricular late potentials assessed by SAECG were found to have higher cardiac Iron load and, thus, lower cardiac T2* MRI conduction time. However, the parameters that were significantly different among patients with variable degrees of cardiac Iron load, such as, QTc and T duration, which indicates the prolongation of the ventricular repolarization phase. Since QTc prolongation is associated with higher mortality, further studies to understand the underlying mechanism of this finding and its importance seem essential [In our study, myocardial and hepatic dry Iron weight had direct and significant correlations with QTssential .In a study conducted by Patsourakos et al., the existence of ventricular late potentials in SAECG was associated with longer QRS duration, longer QT interval, larger left ventricular end-diastolic diameter, larger left atrial volume index, and higher pulmonary artery systolic pressure, all indicating more severe cardiac complications of beta thalassemia major . In our In a study by Franzoni et al., thalassemia major patients underwent Holter ECG monitoring, and patients with ventricular late potentials showed higher rates of ventricular tachycardia, which shows that this method can be used as a screening method for cardiac complications of beta thalassemia major. This is in line with the results of our study that patients with ventricular late potentials in their SAECG need further cardiac evaluations .Isma’eel et al. also evaluated 26 patients with beta-thalassemia major for seven years and assessed them with SAECG. In this period, ferritin levels were correlated with QRS duration and RMS voltage. Therefore, they concluded that these two SAECG parameters could be used as an indicator of Iron overload and cardiac complications .In our study, filtered QRS duration was significantly correlated with the P–R interval. Although atrioventricular blocks are rare in thalassemia major patients and only a few case reports exist in this matter , prolongIn our study, we found that patients with ventricular late potentials assessed by SAECG had a higher myocardial Iron load, and a higher myocardial Iron load is associated with higher cardiac complications in patients with beta-thalassemia major. However, the changes in cardiac function occur in a long term. Consequently, SAECG can be used as a screening test for cardiac complications in beta-thalassemia major patients.