Introduction: Dyspnea is a common complaint in pregnant women with no cardiac and pulmonary diseases. We aimed to assess whether physiological dyspnea of pregnancy was correlated with subtle changes in ventricular systolic and diastolic function.Methods: This cross-sectional study enrolled 40 healthy pregnant women in their second and third trimesters with no complaints of dyspnea and 40 healthy pregnant women in the same trimesters with a complaint of dyspnea. Parameters of echocardiography were compared between the 2 groups. Results: Global left ventricular ejection fraction (59.65±6.44 and 58.49±4.95 P=0.418 in patients without and with dyspnea respectively), and global longitudinal strain were not significantly different . Global circumferential strain (GCS) was lower in patients with dyspnea. . Systolic volume (33.17±8.94 vs 32.63±8.09) and diastolic volume (80.75±18.73 vs 78.37±16.63) and left ventricular end-diastolic diameter (47.5±4.24 vs 46.23±3.21) were not different . Left ventricular end-systolic diameter was significantly lower in the case group . Left atrial area index in the patients with dyspnea was lower. Other findings were a high E/E’ and high pulmonary artery pressure in the patients with dyspnea. Conclusion: Dyspnea in pregnant women can be a consequence of incomplete physiological adaptation to volume overload in pregnancy. Lower systolic and diastolic diameters of the left ventricle, left atrial area, and left atrial index may lead to increased filling pressure, manifested by a higher E/E’ ratio and pulmonary artery pressure. Only 3.2% of women experience severe dyspnea within their first 20 weeks of gestation, with the rate rising to about 37.5% in the third trimester.3 Dyspnea can cause a diagnostic dilemma in pregnant women with previous known cardiac diseases. Multiple causes have been suggested for physiological dyspnea in pregnancy, including anemia, the growing uterus pushing upward on the lungs, increased pulmonary blood volume, and nasal congestion.4 Dyspnea is a common symptom in normal, uncomplicated pregnancies. It is reported in 60% to 70% of normal pregnant women in the third trimester.5 Cardiac output increases secondary to a higher stroke volume. At the beginning of the second trimester, cardiac output increases by 30% to 50% because of an elevation in stroke volume and pulse rate, leading to volume overload.6 Drops in arterial pressure and systemic vascular resistance are features of normal pregnancies and are secondary to the dilatation of the peripheral vessels due to the high levels of progesterone, prostaglandins, and nitric oxide. In addition, the renin-angiotensin- aldosterone system is activated, likely in response to the dilatation of the peripheral vessels and lower blood pressure, and it can cause an increase in vascular tone.7 In addition to increased cardiac preload, reduced cardiac afterload and increased left ventricular mass and ejection fraction have also been reported in pregnant women.8 Globally, cardiovascular diseases complicate 1% to 4% of pregnancies10 and are the main cause of mortality during pregnancy.11 Some cardiovascular diseases such as congenital cardiac diseases, pulmonary hypertension, and ventricular dysfunction can impact the prognosis of mothers and their neonates.9 Thus, understanding the normal remodeling of the maternal heart allows physicians to diagnose and manage abnormal cardiac conditions in early phases. In pregnant women, dyspnea in daily activities can be a symptom of cardiac or pulmonary diseases. Tara et al12 assessed 50 pregnant women with dyspnea and reported that 12% of the cases had pulmonary hypertension and 54% suffered from valvular heart diseases, including mitral valve prolapse and regurgitation. Interestingly, a significant correlation was found between the New York Heart Association functional class and the presence of cardiac valvular diseases or pulmonary hypertension. Changes in the physiology of the cardiovascular system in pregnancy and the risks in the course of pregnancy warrant a different and specific approach to the evaluation and management of cardiovascular conditions. Recent advances have enabled pregnant women with cardiac problems to maintain their pregnancy via close, continuous monitoring. It is, therefore, crucial to precisely evaluate ventricular systolic and diastolic function via echocardiography and measure cardiac dimensions and intracardiac pressures in cases of dyspnea. In the present study, we sought to evaluate changes in left ventricular function in terms of more novel parameters, including left ventricular strain, in addition to other functional parameters of ventricular systolic and diastolic functions, in pregnant women suffering from dyspnea with no known or overt causes of dyspnea and compare them with the same parameters in pregnant women without dyspnea. In normal pregnancies, many physiological and hemodynamic cardiovascular alterations occur for adaptation to transient load changes. In the sixth gestational week, plasma volume rises by about 45%, and the red blood cell mass increases by between 20% and 30%. This case-control study was conducted in our hospital between 2020 and 2021. The study population consisted of pregnant women with and without dyspnea with a gestational age of 13 weeks or more who presented to the obstetric/gynecology clinic for routine examinations. Forty pregnant women without dyspnea and 40 pregnant women with dyspnea of New York Heart Association functional class II or higher were selected via convenience sampling. The inclusion criteria were pregnant women with dyspnea as the case group and those without dyspnea as the control group, who were willing to participate in the study, had no previous history of cardiac and respiratory diseases, and had normal baseline echocardiography and spirometry. The exclusion criteria were composed of history of pulmonary diseases, respiratory infections during pregnancy, anemia, history of chronic conditions , history of the consumption of medications affecting the respiratory system , history of underlying cardiac diseases, structural and congenital abnormalities, and cardiomyopathy at first evaluation. Baseline variables, including age, gestational age, parity, height, weight, body mass index, and medical and drug history, were collected. Dyspnea during pregnancy was defined as a feeling of breath shortness or disturbance in normal breathing that was started during pregnancy and was not caused by new or underlying cardiac or pulmonary diseases. Initial evaluation was performed by physical examination to detect any abnormality in the heart and respiratory systems. The subject’s height, weight, and waist circumference were also measured to exclude the effects of obesity and progressive uterine distention on lung volume. Additionally, routine laboratory tests were done to detect any abnormality. All eligible women underwent transthoracic echocardiography, tissue Doppler ultrasonography, and strain analysis with a Phillips Epic 7 device by an expert echocardiographer who was blind to complaint of dyspnea by the patients. The following variables were collected via echocardiography: left ventricular end- diastolic diameter and volume, left ventricular end-systolic diameter and volume, left ventricular ejection fraction, early and late diastolic mitral inflow velocities (E and A), E/E’ ratio, global circumferential strain (GCS) and global longitudinal strain (GLS), right ventricular end-diastolic diameter and right ventricular systolic calculation via right ventricular peak systolic myocardial velocity (Sm), and tricuspid annular systolic excursion. Finally, left atrial area and pulmonary systolic pressure were calculated, and all the collected data were compared between the 2 study groups. Left ventricular end-diastolic volume, left ventricular end-systolic diameter, left atrial area, and right ventricular end-diastolic diameter were measured by simple 2D echocardiography. E-wave, A-wave, and right ventricular Sm velocities, as well as E/E’, were measured by Doppler echocardiography. In addition, GLS and GCS were measured by automated cardiac motion quantification. The measurement of GLS and GCS was done by using 6 gray scale images that were stored on digital media at the time of the collection of other data with care to avoid foreshortening. Offline analysis was performed, and strain data were generated. Images used for GLS measurement were obtained in 2-, 3-, and 4- chamber views, and images utilized for GCS calculation were acquired in 3 short-axis views at the basal, mid, and apical levels of the left ventricle . The gra Data collection was done by a single skilled echocardiographer. Inter and intraobserver variabilities were tested via random repetitions by the same echocardiographer at 1-month intervals and by a second echocardiographer, who was blind to the first observer’s measurement. Finally, the parameters were compared between subjects with and without dyspnea. The study protocol was approved by the Review Board of cardiology. (IR.TUMS.MEDICINE.REC.1399.977)P value of less than 0.05 was considered statistically significant. Statistical analysis was performed with SPSS, version 23.0. For descriptive analysis, the mean and the standard deviation were reported for quantitative parameters. Frequencies and percentages were used for qualitative variables. For the comparison of parametric and nonparametric variables, the t test and the Mann–Whitney U test were employed, respectively. Further, the χ2 test was drawn upon to compare qualitative variables. A P = 0.965). The mean gestational age was 25.81 ± 7.81 and 29.73 ± 5.67 weeks, respectively, which was significantly higher in the patients without dyspnea (P = 0.015). There were no significant differences in weight, body mass index, and waist circumference between the 2 groups. The entire study population’s baseline characteristics are summarized in  Forty pregnant women with dyspnea and 40 pregnant women without dyspnea were analyzed in our study. The mean age of the subjects with and without dyspnea was 30.57 ± 5.75 and 30.52 ± 4.71 years, respectively (P = 0.03). Systolic and diastolic volume and left ventricular end-diastolic diameter were not different between the 2 groups, whereas left ventricular end-systolic diameter was significantly lower in the case group (P = 011). Interestingly, left atrial area and left atrial volume index in the patients with dyspnea were lower than those in the control group . Although relative wall thickness was within the normal range in both groups, the women with dyspnea showed a trend for higher relative wall thickness (P = 0.08). Left ventricular mass and left ventricular mass index were not significantly different between the 2 groups . Other scintillating findings were a high E/E’ and a high pulmonary artery pressure in the patients with dyspnea compared with the control group . to detect by routine echocardiography; nonetheless, it causes symptoms of dyspnea in pregnant women. A lower GCS is another finding that should be considered as a cause of dyspnea in pregnancy. The study population’s echocardiographic variables are presented in detail in  Evaluation of echocardiographic parameters showed that while global left ventricular ejection fraction and GLS were not significantly different between the 2 groups , GCS was lower in the patients with dyspnea, compatible with mild left ventricular systolic dysfunction . Goland and colleagues also reported that left ventricular end-systolic diameter was lower in their patients with dyspnea than in their controls, but this decrease failed to constitute statistical significance. The results of the current study revealed that mean GCS in pregnant women with dyspnea decreased significantly compared with healthy pregnant women, while changes in GLS index were not significant and this subtle abnormality of LV function which is not still evident in other parameters as GLS might be the cause of dyspnea in pregnant women who appears normal in 2-dimensional echocardiography. Assessment of the other structural and functional parameters of the left ventricle in pregnant women with dyspnea showed significantly larger relative wall thickness, E/e’ ratio, and pulmonary artery pressure and significantly lower left ventricular end-systolic diameter, left atrial area, and left atrial area index by comparison with the control group. In addition, left ventricular end-diastolic diameter and left atrial size were lower in the group with dyspnea than in the controls, but this difference was not statistically significant. Our results are in line with some previous reports. Goland et al Physiologically, the enlargement of cardiac chambers is expected due to an elevated blood volume in pregnancy. Nevertheless, we found that although cardiac chamber size in both groups was within the normal range, the group with dyspnea had a significantly lower chamber size than the group without dyspnea. On the other hand, a significant rise in the ventricular diastolic index of E/E’ in pregnant women with dyspnea can reflect degrees of myocardial stiffness and higher left ventricular end-diastolic pressure. Hence, we conclude that the increase in cardiac chamber size is a physiological adaptation to maintain left ventricular end- diastolic pressure within the normal range and in some pregnant women, this adaptation is not enough, leading to physiological dyspnea of pregnancy.4 having evaluated clinical and echocardiographic parameters in pregnant women with dyspnea, reported a significant increase in left ventricular end-diastolic diameter and pulmonary artery pressure and a decrease in left ventricular end-systolic diameter in the presence of dyspnea compared with controls. Some other studies have also reported a reduction in ventricular diameters among pregnant women with dyspnea. Barut et al,19 Among these strain values, GCS index is a sensitive parameter for regional myocardial function. Tamrat et al20 reported a significant fall in GCS among pregnant women with peripartum cardiomyopathy in spite of normal ejection fraction and left ventricular end-diastolic diameter. Additionally, GLS exhibited a drop in comparison with controls, but this reduction was nonsignificant. A reduction in left ventricular strain parameters, consisting of GLS, GCS, and GRS, in pregnant women with gestational hypertension and severe or early preeclampsia has been reported.21 Sugahara et al22 reported significant decreases in ejection fraction, GLS, and GCS and increases in left ventricular systolic and diastolic diameters among pregnant women with peripartum cardiomyopathy. Another study also evaluated cardiac abnormalities in different pregnancy trimesters and compared the findings with those in nonpregnant women. Another theory for the justification of physiological dyspnea in pregnancy is a subtle reduction in left ventricular function that is not detectable with a simple assessment of ejection fraction. The measurement of cardiac strain values by speckle-tracking echocardiography can provide precise information on regional and global disturbances in the function of ventricular contractions. These strain values are measured in longitudinal and circumferential dimensions.23 There are only a few studies on the association between changes in cardiac parameters and dyspnea in pregnancy, and our results are consistent with their findings.18 The results revealed that with advances in gestational age, ejection fraction, GLS, and GCS decreased, while left ventricular systolic and diastolic diameters and relative wall thickness index increased. A lower left ventricular end-systolic diameter, a lower left atrial area, a higher E/E’, and a higher pulmonary artery pressure make this hypothesis probable that physiological adaptation through an increase in the size of the heart chambers is not enough in some pregnant women to meet the higher blood volume of pregnancy and ultimately leads to a higher left ventricular end-diastolic pressure and a higher pulmonary artery pressure. The elevation in left ventricular end-diastolic pressure and pulmonary artery pressure is too subtle The limitation of our study is its relatively small sample size. Larger study populations with the application of spirometry may yield more comprehensive results. Another limitation of our study is the use of NYHA FC for assessing the presence of dyspnea as opposed to scales such as Dyspnea VAS etc. Dyspnea in pregnant women can be a consequence of incomplete physiological adaptation to volume overload in pregnancy. Lower systolic and diastolic diameters of the left ventricle, left atrial area, and left atrial index may lead to increased filling pressure, manifested by a higher E/E’ ratio and pulmonary artery pressure. However, subtle systolic dysfunction, indicated by a low GCS value, should be considered as well.Conceptualization: Atoosa Mostafavi, Seyed AbdolhusseinTabatabaei.Methodology: Atoosa Mostafavi, Seyed Abdolhussein Tabatabaei,Seyede Zahra Fatook Kiaei.Validation: Atoosa Mostafavi, Seyed Abdolhussein Tabatabaei,Seyede Zahra Fatook Kiaei.Formal Analysis: Seyede Zahra Fatook Kiaei, Atoosa Mostafavi,Seyed Abdolhussein Tabatabaei, Mona Feizian.Investigation: Seyede Zahra Fatook kiaei, Atoosa Mostafavi, SeyedAbdolhussein Tabatabaei, Mona Feizian.Resources: Seyede Zahra Fatook Kiaei, Atoosa Mostafavi, SeyedAbdolhussein Tabatabaei, Mona Feizian.Data Curation: Seyede Zahra Fatook Kiaei, Atoosa Mostafavi, SeyedAbdolhussein Tabatabaei, Mona Feizian.Writing—Original Draft Preparation: Mona Feizian, AtoosaMostafavi.Visualization: Atoosa Mostafavi.Supervision: Atoosa Mostafavi.Project Administration: Atoosa Mostafavi, Seyed AbdolhusseinTabatabae.Funding Acquisition: Atoosa Mostafavi, Seyed AbdolhusseinTabatabae. The authors declare that there are no funding supports. The study protocol was approved by the Review Board of cardiology. (IR.TUMS.MEDICINE.REC.1399.977) The authors declare that there are no conflicts of interest regarding the publication of this article.


BackgroundAn interplay of myocardial structural abnormalities and coronary arterial dysfunction underlies the worsening left ventricular compliance. The conventionally used angina drugs have demonstrated a beneficial effect on both angina and coronary flow in cases with microvascular dysfunction and non-obstructive coronary disease. Despite that, vasoactive therapy only partially affects diastolic function in this patient population.PurposeThis retrospective study was planned to evaluate the association of myocardial mass, delayed epicardial coronary flow, and vasoactive drugs with parameters of diastolic function in two cohorts with preserved left ventricular function and non-obstructive coronary disease in patients with slow coronary flow phenomenon (SCFP) and patients with the hypertensive disease and left ventricular hypertrophy.Material and methodsLVH). The remaining 15 (31.3%) were patients with ventricular hypertrophy, hypertension, and non-delayed epicardial coronary flow (NFLVH).The epicardial coronary flow was evaluated in 48 patients with unstable angina in the absence of coronary stenosis >50%, by applying the methods of corrected thrombolysis in myocardial infraction frame count (cTFC). The abnormalities in the left ventricular function were assessed by echocardiography using PW-Doppler of the diastolic mitral inflow and tissue Doppler imaging. Twenty-one (43.8%) patients were diagnosed with SCFP, and twelve patients (25%) had slow epicardial coronary flow, hypertensive disease, and ventricular hypertrophy  when compared to SCFP  and NFLVH . A borderline significant difference was observed for the peak early diastolic septal mitral annular velocity (e’S) between the patients with SFLVH and SCFP . The ratio of mitral diastolic inflow velocity to early diastolic velocity of the mitral annulus (E/e’) in the SFLVH group was a tendency higher than E/e’ of the patients with SCFP  and NFLVH  .In the group with left ventricular hypertrophy, E/e’ >10 was more frequently observed in patients with a marked delay in the epicardial flow  and higher left ventricular mass .The patients with SFConclusionsPatients with microvascular angina represent a diverse population. The echocardiographic parameters of left ventricular relaxation (e') and end-diastolic pressure (E/e’) are abnormally altered in the population with left ventricular hypertrophy compared to SCFP. The delayed epicardial flow further impairs diastolic function in hypertensive patients with hypertrophy and non-obstructive coronary disease. Studies in cohorts with heart failure with preserved ejection fraction (HFpEF) in the absence of coronary atherosclerosis have observed a stiffer left ventricle and reduced longitudinal systolic function in patients with pronounced epicardial coronary flow abnormalities ,2. In adMajor classes of conventionally used angina drugs have demonstrated beneficial effects on ischemia and coronary flow in cases with microvascular dysfunction and non-obstructive coronary disease. Nevertheless, the medications only partially affect diastolic function in this patient population -7.Thus, this retrospective study was designed to evaluate the association of myocardial mass, delayed epicardial coronary flow, and vasoactive drugs with parameters of diastolic function in two cohorts with preserved left ventricular function and non-obstructive coronary disease. Specifically, the two cohorts included patients with slow coronary flow phenomenon (SCFP) and patients with hypertensive disease and left ventricular hypertrophy.Тhis research consisted of a single-center, cohort, retrospective study. The study group consisted of 48 patients. Only patients diagnosed with non-obstructive coronary disease (defined as the absence of coronary stenosis of >50% at the time of quantitative coronary angiography) were included in the study. The patients were admitted with unstable angina to the University Hospital 'Alexandrovska’ in Sofia between 2006 and 2008. Thirty-nine patients (70%) underwent symptom-limited exercise stress electrocardiographic tests on the modified Bruce protocol in this clinic prior to angiography . The diaEpicardial coronary flow was evaluated by using the corrected thrombolysis in myocardial infarction (TIMI) frame count (cTFC) method . This meAll of the patients underwent standard echocardiography . The echocardiography was performed in accordance with the recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging ,13. The The following diastolic function indices were determined: early (E-wave) and late (A-wave) maximal rates of the left ventricular diastolic filling ; the time of attenuation of the E-wave (deceleration time [DT]); and peak early diastolic mitral annular septal (e’s) and lateral (e’L) velocities. Left ventricular hypertrophy (LVH) was defined as a thickness of the ventricular septum (IVS) or the posterior wall (LVPW) of the left ventricle ≥12 mm on echocardiography, as well as myocardial mass greater than 95 g/m2 for the female patients and greater than 115 g/m2 for the male patients. The myocardial mass was calculated by using the linear method:0.8x1.04 х [(EDD-IVS-LVPW)3 - EDD3]+0.6 grams;EDD was the dimension of the left ventricle at end-diastole. The myocardial mass of each patient was divided by the body surface area.In our study report, we used the phrases ‘left ventricular hypertrophy subsequent to systemic hypertension' or ‘left ventricular hypertrophy related to systemic hypertension’ to address this specific alteration in heart structure as part of the complex pathologies that are induced by systemic hypertension and included the term ‘hypertensive heart disease.’The exclusion criteria for the study included previous coronary revascularization procedures, thrombolytic therapy for myocardial infarction, left ventricular systolic dysfunction (LVEF <50%), wall motion abnormalities at rest, cardiomyopathy, coronary aneurysm, ectasia and fistula, valve disease, acute or chronic inflammatory disease, recent fracture or surgical procedures, and any type of shock and neoplastic disease. In addition, cases with suboptimal angiographic or echocardiographic imaging study results were also excluded from the study.All of the patients signed written informed consent forms for all diagnostic tests. This retrospective study was approved by the Ethics Committee of University Hospital ‘Alexandrovska’  and complied with the Declaration of Helsinki.The analysis of the data was performed by using SPSS version 19.0 . Categorical variables were presented as counts and percentages, and continuous variables were presented as the mean and SD. Categorical variables were analyzed via the chi-squared test or Fisher’s exact test. The normality of the continuous variables was tested by using the Kolmogorov-Smirnov and Shapiro-Wilk tests. Depending on the results of Levene’s test, the variables with a normal distribution were compared with the Student’s t-test or the Welch test. The nonparametric variables were analyzed with the Mann-Whitney test. One-way ANOVA was applied to evaluate the difference between three continuous variables. Associations with α <0.05 were considered to be statistically significant.LVH and NFLVH more frequently used  diuretics and less frequently used antiplatelet therapy than those with SCFP  of SFLVH and SCFP. Moreover, the filling pressures (E/e’) in the SFLVH tended to be higher than the E/e’ of the patients with SCFP and NFLVH  when compared to SCFP and NFH Figure -3.Increased early mitral inflow velocity and reduced longitudinal septal function (e's) corresponded to the presence of left ventricular hypertrophy in the entire non-obstructive disease cohort Table .Diastolic function parameters were similar in the slow coronary flow patients and those with left ventricular hypertrophy with the normal flow Table .In the group with SCFP and the entire study group, E/e’ in the highest tertile (E/e’>10) was not dependent on either coronary flow velocity or myocardial mass. In the presence of left ventricular hypertrophy, E/e’>10 was more frequently observed in patients with a marked delay in epicardial flow and higher left ventricular mass. In the group with delayed epicardial flow (including SCFP and patients with slow flow in the presence of LVH), E/e’ was significantly related only to the elevated myocardial mass Table .The majority of patients were using bisoprolol or metoprolol (92.9%) as monotherapy or combined with one of the following calcium channel blockers: amlodipine, felodipine, or lercanidipine 97.6%). None of the patients used first-generation dihydropyridines . One patient was on therapy with oral verapamil hydrochloride; the other two patients were on therapy with a first-generation β-blocker (atenolol). The β-blocker of the third generation (nebivolol) was included in the treatment regimen along with the CCB of one participant. The intake of diuretics was not associated with a lower preload . The difference in diastolic function parameters in relation to the vasoactive therapy used in the groups with SCFP and patients with LVH could not be discussed due to the small sample size. However, the early-diastolic septal and lateral mitral annular velocities seemed to be substantially reduced. E/e’ was higher in the patients with LVH on therapy with β-blocker with nitrate compared to these variables in the LVH subgroup taking β-blocker alone or combined with a calcium blocker  was found to be weakly correlated in studies with invasive indices of relaxation  . HoweverAccording to earlier studies, the epicardial coronary flow in cases with left ventricular hypertrophy was frequently characterized as being delayed at angiography , which iIt has been recently reported that the epicardial coronary arterial lumen volume to LV mass ratio modified the coronary arterial resistance in the presence of only minimal coronary disease . Our resIn agreement with previous findings ,25,26, oThe cases of uncertain prognostic accuracy of E/e’   were excPatients with microvascular angina represent a diverse population. The echocardiographic parameters of left ventricular relaxation (e’) and end-diastolic pressure (E/e’) are abnormally altered in the population with left ventricular hypertrophy compared to those in SCFP. The delayed epicardial flow further impairs diastolic function in hypertensive patients with hypertrophy and non-obstructive coronary disease.


Background: This study challenges state-of-the-art cardiac amyloidosis (CA) diagnostics by feeding multi-chamber strain and cardiac function into supervised machine (SVM) learning algorithms. Methods: Forty-three CA ), 20 patients with hypertrophic cardiomyopathy ) and 44 healthy controls ) received cardiovascular magnetic resonance imaging. Left atrial, right atrial and right ventricular strain parameters and cardiac function generated a 41-feature matrix for decision tree (DT), k-nearest neighbor (KNN), SVM linear and SVM radial basis function (RBF) kernel algorithm processing. A 10-feature principal component analysis (PCA) was conducted using SVM linear and RBF. Results: Forty-one features resulted in diagnostic accuracies of 87.9% (AUC = 0.960) for SVM linear, 90.9%  using RBF kernel, 84.9% (0.970) for KNN, and 78.8% (0.787) for DT. The 10-feature PCA achieved 78.9% (0.962) via linear SVM and 81.8% (0.996) via RBF SVM. Explained variance presented bi-atrial longitudinal strain and left and right atrial ejection fraction as valuable CA predictors. Conclusion: SVM RBF kernel achieved competitive diagnostic accuracies under supervised conditions. Machine learning of multi-chamber cardiac strain and function may offer novel perspectives for non-contrast clinical decision-support systems in CA diagnostics. Cardiac amyloidosis (CA) is a rare restrictive cardiomyopathy, characterized by an uncontrolled amyloid protein deposition that exacerbates organic function . Early CCardiac magnetic resonance (CMR) imaging plays an important role in CA diagnosis and CA differentiation from other hypertrophic diseases such as hypertrophic cardiomyopathy (HCM). Despite clinical and radiological advances, CA remains a challenging diagnosis usually confirmed by specialized centers with significant delay in the patient’s clinical odyssey. The state-of-the-art CA diagnosis via CMR is ideally substantiated by diffuse sub-endocardial or transmural late gadolinium enhancement (LGE), elevated myocardial native T1, elevated extracellular volume fraction and the inability of myocardial signal suppression in phase-sensitive inversion recovery (PSIR) LGE sequences . Their iHowever, recent investigations have shown that cardiac strain provides discriminative value for all cardiac chambers and thus may support differentiation of CA from hypertrophic cardiomyopathy (HCM) and healthy control subjects (CTRL) ,13,14,15The complexity of this diagnostic approach, encompassing a wide spectrum of parameters, demands the computational gold standard termed machine learning. Machine learning is a function of artificial intelligence, used as a promising alternative to overcoming the limitations of traditional prediction approaches . Recent This study has a retrospective single-center observational design. The inclusion criteria called for biopsy-validated CA patients and their subtypes. CA patients had received a routine CMR according to standard diagnostic protocol with adequate imaging quality. HCM patients were enrolled upon confirmed diagnosis in accordance with ESC guidelines 2014 . A groupIn adherence to the study objective, the included variables were selected based on a profound array of strain and strain rates of the RA, LA and RV. For both atria, this resulted in reservoir, conduit and booster longitudinal strain and strain rate in the two- and four-chamber view. For the right ventricle, circumferential, radial and longitudinal strain and strain rate were quantified in the short-axis and four-chamber view. Lastly, in addition to demographic parameters such as age and body surface area, general cardiac functions were included, such as age, body surface area, heart rate, right heart volumetrics, and left and right ventricular ejection fraction were included. In sum, 41 different variables were available for this study.All subjects underwent cardiac MRI at our institution using a 3.0 Tesla multi-transmit magnetic resonance imaging system  incorporating dStream technology. Vector electrocardiogram-triggered cardiac cine acquisitions were performed on all patients. The maximum gradient performance was 40 mT/m with a slew rate of 200 mT/m/ms. A cardiac phased-array coil was used for signal reception. An axially acquired stack covering the whole heart, a short-axis stack covering the entire left and right ventricles  as well as standard two-, three- and four-chamber views were utilized with retrospectively gated cine steady-state free-precession acquisitions (TR/TE/flip angle = 2.7 ms/1.35 ms/42°) for the assessment of heart function in all four cardiac chambers and morphology. A parallel imaging technique with a SENSE-reduction factor of 2 was applied to keep breath-holding times ≤ 12 s. Within one cardiac cycle >25 reconstructed heart frames were acquired in order to achieve greater temporal resolution, as recently demonstrated . The spa® software package  based on cine steady-state free-precession acquisitions. LA and RA feature-tracking techniques were applied as previously described [Strain analysis was conducted using the CVI42escribed . The lonDescriptive statistics were processed in SPSS . All continuous variables were presented as mean ± standard deviation (SD) when normally distributed, otherwise as median with interquartile range (IQR). Comparison of baseline characteristics, volumetric parameters and cardiac strain between three different groups was carried out using the univariate ANOVA or ANOVA–Welch test if the criteria were met. A post-hoc Tukey HSD was conducted in case of homogeneity of variance, otherwise a Games–Howell was used to identify inter-group differences. In case of nonparametric data, the Kruskal–Wallis test was used.For the linear correlation, a matrix was generated. The matrix displays the correlation coefficient for different variables. Numbers in the matrix varied from −1 to +1. A number closer to +1 indicates a strong positive correlation, a number closer to −1 indicates a strong negative correlation and 0 demonstrates no correlation between the features. Initially, the data were normalized for all features. Normalizing the data reduces the bias caused by larger-scale data. The correlation matrix was generated using Pearson’s product–moment correlation.Multiple machine learning classifier algorithms such as k-nearest neighbor (KNN), support vector machine (SVM) linear, SVM kernel RBF, and decision tree (DT) were used on the dataset as recently described in literature ,25. The Processing of variables for the mentioned algorithms was performed using Python (Version nr. 3.8.12). This study implemented a linear and radial basis function (RBF) SVM, KNN and DT for MRI data analysis. Their basic function is illustrated in The algorithm, referred to as radial basis function (RBF) kernel, is characterized as a pattern analysis algorithm that utilizes specific vectors referred to as “input spaces” to quantify the degree of similarity between two data points. The RBF kernel value ranges from zero to one. Similarity between points would result in the RBF kernel value being closer to zero, two dissimilar points shift the RBF kernel value closer to 1. Precision , recall score (sensitivity) and F1-score (test accuracy) were calculated. To calculate the AUC, the one vs. rest (ovr) method was used to evaluate multiclass models by comparing each class against all other classes at the same time.The KNN algorithm  was usedA decision tree is another supervised machine learning algorithm that is used in both regression and classification problems. In this algorithm, the data is continuously split based on various parameters, and it can be explained by entities such as decision nodes and leaves. The same training and testing methodology were applied to both KNN and DT.Principal component analysis is a dimensionality reduction method widely used to reduce the dimensionality of large datasets with a large number of variables improving cost-effectiveness and efficiency while preserving as much ‘variability’  as possible . Featurep < 0.001). Moreover, CA-associated impairment of cardiac strain was observed in various chambers, for example for the reservoir phase of both atria , p < 0.001; LA (four-chamber); HCM: 14.7 ± 7.1% vs. CA: 7.0% , p < 0.001). All features are summarized in This retrospective study enrolled a total of 107 subjects, including 43 CA patients, 20 HCM patients and 44 CTRL patients. CA patients made up the oldest cohort  in contrast to HCM (63.9 ± 7.4 years) and CTRL ). CA patients showed significantly impaired ejection fraction for both the left and right ventricle compared to CTRL and HCM  for the KNN algorithm, 78.8% (0.787) for the DT algorithm, 87.9% (AUC: 0.962) for SVM linear algorithm and 90.9% (AUC: 0.996) for the SVM RBF kernel .SVM RBF kernel presented the highest accuracy rate among all employed methods, which is why it was the algorithm of choice for PCA. Corresponding confusion matrices and classification reports were generated for all four classifier algorithms . Confusip ≤ 0.003; The variance across principal components  found thThe confusion matrix for PCA using the SVM RBF algorithm is summarized in To the best of our knowledge, this study is the first to report a supervised machine learning diagnostic approach via CMR left atrial, right atrial and right ventricular quantified strain and general cardiac functions. The novel findings of the present study are as follows: (i) supervised machine learning accurately differentiates CA within a cohort of HCM patients and CTRL subjects, (ii) larger datasets cumulatively contribute towards discriminative performance, (iii) LV-EF and RV-EF remain important feasible clinical predictors of CA due to their routine availability.A recent left ventricular multiparametric assessment of 41 CA and 45 HCM patients found the diagnostic accuracy-associated AUC to be 82% for percentage normal myocardial strain, 81% for atypical LGE and 94% for the combination of both . A furthThe recent integration of machine learning has presented promising gadolinium-free aspects for CA diagnostics. For example, Huang et al. highlighted the potential diagnostic function of texture analysis. A diagnostic accuracy of 82.2% was observed based on seven texture features of the widely available T2-weighted images for CA differentiation from HCM in a similar hypertrophy subgroup using the machine learning algorithm . A similThe choice of classifier algorithm is constantly challenged, as performance is dependent on the complexity and distribution of the dataset. Our results showed that diagnostic accuracy varies depending on the classifier used. In this case, utilizing the SVM linear is simpler and more efficient than RBF, although it results in lowered diagnostic performance as data is not always linearly separable. Although RBF shares advantages with KNN, it often remains superior by overcoming the space complex problem. The power of the RBF kernel lies in its ability to map points in higher-dimensional spaces, which appears best suited for our dataset.As anticipated, higher diagnostic accuracies are obtained with the 41-variable model; however PCA-associated reduction to a quarter of the variables comes at a cost of only an 8.9% loss in diagnostic accuracy. Thus, depending on the time and effort for parameter quantification the appropriate model can be selected. Moreover, the majority of features in the PCA model were based on left and right atrial strain parameters. Impairment of nearly all functional phases for left and right atrial longitudinal strain appears to be a further valuable discriminative characteristic contributing towards diagnostic accuracy, as previously observed for the left atrium . AdditioIntegration of machine learning in medical diagnostics will increase in the future as its efficiency for processing large clinical datasets cannot be matched by human cognition. We present an exemplary study in which supervised machine learning of multi-chamber MRI quantified volumetrics and strain data achieved CA prediction for a 41- and 10-variable dataset. Depending on the classifier algorithm employed, diagnostic accuracies ranged from fair to excellent . In thisThis study is based on a retrospective single-center observational design with typical limitations. The cohorts were not matched, although only healthy subjects above the age of 50 years were included in an attempt to provide greater homogeneity. Moreover, this approach remains an unsupervised algorithmic model. The extent to which this model is applicable in an unsupervised setting is not established. Furthermore, the cohort primarily includes CA patients in advanced stages of the disease and cannot account for early-stage disease detection. Algorithms cannot establish a cause–effect. They can however recognize numerical patterns that emerge from large datasets in order to deliver supportive output to the physician in clinical practice. However, this remains a preliminary study, which requires validation using larger datasets and further risk assessment. Risk assessment can be conducted using a multicriteria decision analysis (MCDA) ,36.Machine learning for a large and a small dataset of RA, LA and RV cardiac strains and functional parameters presents competitive diagnostic accuracies for CA detection when compared to the state-of-the-art methods. The observations of our scientific challenge may introduce new perspectives in non-contrast CMR diagnostics with the potential of clinical decision-making support. The support vector machine algorithm using a radial basis function kernel was found to be the most efficient subheading algorithm achieving competitive diagnostic accuracies under supervised conditions.


The superior and inferior tarsal muscles are sympathetically innervated smooth muscles. Long-term diabetes often leads to microvascular complications, such as, retinopathy and autonomic neuropathy. We hypothesized that diabetes induces (1) sympathetic paresis in the superior and inferior tarsal muscles and that this measure is associated with (2) the severity of diabetic retinopathy, (3) the duration of diabetes, and (4) autonomic function. In addition, association between the severity of retinopathy and autonomic function was investigated.Forty-eight participants with long-term type 1 diabetes and confirmed distal symmetrical polyneuropathy were included. Palpebral fissure heights were measured bilaterally in response to topically applied 10% phenylephrine to the right eye. The presence of proliferative diabetic retinopathy (PDR) or nonproliferative diabetic retinopathy and disease duration were denoted. Time and frequency derived heart rate variability parameters obtained from 24-hour continuous electrocardiography were recorded.P = 0.001). The ∆PFH was significantly lower in the PDR group (0.41 mm ± 0.43 vs. 1.27 mm ± 1.0), F = 5.26, P = 0.011. The ∆PFH was lower with increasing diabetes duration, r(37) = −0.612, P = 0.000. Further, the ∆PFH was lower with diminished autonomic function assessed as total frequency power in electrocardiogram , and sympathetic measures of very low  and low frequency power .The difference in palpebral fissure heights between phenylephrine treated and untreated eyes (∆PFH) was 1.02 mm ± 0.29 (The ∆PFH is a simple ambulatory sympathetic measure, which was associated with the presence of PDR, disease duration, and autonomic function. Consequently, ∆PFH could potentially be an inexpensive and sensitive clinical indicator of autonomic dysfunction. Sensory-motor and autonomic neuropathies are well-described microvascular complications to long-term diabetes. Major clinical manifestations of diabetic autonomic neuropathy (DAN) include impairment of the nervous supply to the heart, gastrointestinal tract, and urogenital systems, as well as impaired neurovascular function.–The superior and inferior tarsal muscles are sympathetically innervated smooth muscles involved in sustaining eyelid retraction. The innervation originates from nerve fibers in the superior cervical ganglion. Consequently, topical application of phenylephrine, a sympathomimetic drug, causes an increase in palpebral fissure height (PFH) in healthy subjects of 1.2 to 1.6 mm accordingly.,Bilaterally diminished PFH is indicative of sympathetic paresis. The interpretation of this measure is more straightforward than evaluating pupillary responses, because the pupil receives dual sympathetic and parasympathetic innervation. Nevertheless, pupillary denervation hypersensitivity to pilocarpine has shown to be an indicator of early DAN,,Topical application of the alpha-adrenergic agonist phenylephrine in one eye provides the possibility of evaluating the pupillary sensitivity and PFH difference between the two eyes (∆PFH), which could serve as an indicator of sympathetic function. For example, miosis is associated with cardiac vagal dysfunction and somatic sensory loss.–,Another common microvascular complication of diabetes mellitus is DR. Because it shares the same pathogenesis, it is not surprising that several studies have shown associations between severity of retinopathy and autonomic function.Consequently, we hypothesized that long-term diabetes induces sympathetic paresis in the peripheral sympathetic nerve fibers innervating the superior and inferior tarsal muscles. Thus, the aim of this study was to (1) quantify the sympathetic paresis by assessing eye-to-eye differences in PFH (∆PFH) after topical application of 10% phenylephrine and to associate this measure with (2) the severity of DR, (3) disease duration, and (4) autonomic function in patients with long-term diabetes. In addition, we investigated (5) the association between autonomic function and the severity of DR.These data are secondary analyses of baseline assessments in a larger randomized clinical trial, registration number .PFH is defined as the vertical palpebral aperture height between the upper and lower eyelid margin in the pupillary plane of the eyes in the primary position of gaze. PFH was measured on both eyes by standardized frontal view photograph, 15 minutes after instillation of two drops of phenylephrine hydrochloride 10%  into the inferior fornix of the right eye. A scale bar was placed between the subject's eyes to allow accurate life-size measurements 2. The diParticipants were dichotomized into proliferative DR (PDR) and nonproliferative DR (NPDR) groups by the presence  or absence of neovascularization, respectively. Neovascularization is defined by the formation of new blood vessels originating from the retina and extending to the vitreoretinal interface and potentially into the vitreous. The presence of neovascularization was identified by visual inspection of fundus photos and optical coherence tomography scans. The same trained ophthalmologist and photographer performed all assessments to minimize interobserver bias. In accordance with the Danish diabetes program, individuals with diabetes are referred to a private practitioner in ophthalmology and recommended to participate in yearly checkups. If and when treatment is needed , patients are referred to a hospital where these measurements were conducted. Therefore, patients who have made use of this recommendation are diagnosed and followed systematically in a secondary center, and the diagnosis was confirmed at the hospital. For patients who have not made use of this recommendation, the diagnosis was made upon examination at the hospital.,The current study used the definition published by Shaffer et al.t tests. Differences in ∆PFH between the PDR and NPDR groups were tested using an independent samples t test. Associations between ∆PFH, disease duration, and cardiovascular autonomic function were tested using Pearson's correlation coefficient. Heart rate variability parameters were adjusted for resting heart rate at the time of testing. To test for differences in cardiovascular autonomic function and severity of DR, one-way ANOVA was used. A P value of 0.05 or less was considered significant.Data handling and statistical computations were carried out using SPSS 25.0.0 . All data are presented as arithmetic means ± standard deviation or as medians with interquartile range depending on the distribution of the data. Data were tested for normality by visually inspecting histograms, Q–Q plots, as well as by Shapiro–Wilk testing. The average PFH for the right and left eye were calculated and compared using independent samples The characteristics of the study group are shown in P = 0.001), indicating tarsal muscle response after the stimulation of adrenergic receptors. The ∆PFH was significantly lower in the PDR group (0.41 ± 0.43 mm vs. 1.27 ± 1.0 mm), F = 5.26, P = 0.011 (P = 0.000 (P = 0.014), VLF , and LF , indicating an association between the degree of sympathetic paresis and sympathetic regulation of the heart. No associations were found in time-domain parameters. Heart rate variability measures are shown in Instillation of 10% phenylephrine in the right eye resulted in increased eyelid retraction providing a ∆PFH of 1.02 ± 0.29 mm   see , indicatThe difference in PFH, measured as ∆PFH, between topically applied phenylephrine and no treatment showed positive associations to the LF content of heart rate variability parameters, primarily representing sympathetic tone. In this specific cohort with established diabetic polyneuropathy, the ∆PFH could potentially act as an indicator of the presence or lack of sympathetic reserve capacity, which again was associated with severity of DR and diabetes duration. The method seemed sensitive to assess the function of the sympathetic fibers, because significant differences between the treated and untreated eyes were present. We believe this is the first time this simple and inexpensive sympathetic response is measured in a cohort with diabetes and verified diabetic polyneuropathy. Our findings may indicate its usefulness as a screening tool; we showed associations with established heart rate variability measures of autonomic function. However, we cannot conclude whether the method is useful in the early stages of diabetic polyneuropathy, where sympathovagal balance is less affected.,,DAN leads to sympathetic paresis characterized by miosis and ptosis.,Moreover, the expression of α1D-, α2C- and β2-receptors in the superior tarsal muscle in ptotic patients have been reported in descending order–.Our intention was to show whether a very simple method could make a general autonomic neuropathy probable, and thus the used method should be translated easily into daily clinical practice. Although Müller's muscle is admittedly dependent on sympathetic stimulation, it can also be influenced by other factors such as gaze direction, flexion or extension of the neck, and orbicularis oculi tone. We found a small, although highly significant difference in PFH between the treated eye and the untreated eye (∆PFH), in accordance with the measures reported by Bastiaensen et al.Furthermore, this diminished reserve capacity was more evident in the PDR group in comparison with the NPDR group, indicating pronounced microvascular complications, and these alterations were furthermore associated with diabetes duration. To our knowledge, this study is the first time such associations have been reported.Finally, we showed a positive association between the simple ∆PFH and advanced heart rate variability frequency measures, VLF (0.0033–0.04 Hz) and LF (0.04–0.15 Hz), which plausibly indicate the systemic sympathodenervation The understanding and impact of LF heart rate variability are, however, controversial. For example, if the LF component reflects the sympathetic cardiac tone, interventions that increase the sympathetic drive should increase the LF power. An increase in LF power has been shown by inducing myocardial ischemia,These interpretations are further supported by the absence of associations between the ∆PFH and HF content, the LF/HF frequency ratio, and the RMSSD, which generally is accepted to reflect parasympathetic content. Still, the definitions of the heart rate variability bands have changed over the years, making study comparisons difficult.,,,–,,,Not surprisingly, several studies have found associations between severity of DR and autonomic dysfunction in type 1The major strength of this study is the ability to associate the introduced novel measure to existing validated autonomic measures of heart rate variability indicative of autonomic function. There are, however, several limitations to our study. First, no frontal photograph was taken before the phenylephrine test, allowing for assessments of pre-existing asymmetry. A previous study investigating PFH asymmetry in primary gaze did not show an affinity to one eye over the other.The ∆PFH was associated with the severity of DR, disease duration, and validated heart rate variability parameters related to predominantly LF content primarily representing the sympathetic content of the sympathovagal balance in patients with type 1 diabetes and confirmed polyneuropathy. Hence, ∆PFH, a simple ambulatory measure, could potentially be a sensitive clinical indicator of autonomic dysfunction.


Background: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is increasingly being recognized as a cause of left ventricular (LV) hypertrophy (LVH) and progressive heart failure in elderly patients. However, little is known about the cardiac morphology of ATTR-CM and the association between the degree of TTR amyloid deposition and cardiac dysfunction in these patients. Methods: We studied 28 consecutive patients with ATTR-CM and analyzed the relationship between echocardiographic parameters and pathological features using endomyocardial biopsy samples. Results: The cardiac geometries of patients with ATTR-CM were mainly classified as concentric LVH (96.4%). The relative wall thickness, a marker of LVH, tended to be positively correlated with the degree of non-cardiomyocyte area. The extent of TTR deposition was positively correlated with enlargement of the non-cardiomyocyte area, and these were positively correlated with LV diastolic dysfunction. Additionally, the extent of the area containing TTR was positively correlated with the percentage of cardiomyocyte nuclei stained for 8-hydroxy-2′deoxyguanosine, a marker of reactive oxygen species (ROS). ROS accumulation in cardiomyocytes was positively correlated with LV systolic dysfunction. Conclusion: Patients with ATTR-CM mainly displayed concentric LVH geometry. TTR amyloid deposition was associated with cardiac dysfunction via increased non-cardiomyocyte area and ROS accumulation in cardiomyocytes. Cardiac amyloidosis (CA) is an infiltrative secondary cardiomyopathy in which proteins with unstable tertiary structures misfold, aggregate, and form congophilic amyloid fibrils that deposit with a range of misfolded fibrillar proteins in the heart ,2,3,4,5.Transthyretin (TTR) is known as prealbumin, and its function is to transport thyroxine and retinol-binding protein. TTR is synthesized mainly by the liver and circulates as a homotetramer . In ATTRIn this study, to identify the LVH geometry and investigate the mechanism of LV dysfunction in patients with ATTR-CM, we evaluated the pathological features, cardiac morphology, and function using human endomyocardial biopsy samples.TTR gene was performed for 17 consenting patients with ATTR-CM. All exon regions of the gene were sequenced using Sanger sequencing.We included 40 consecutive CA patients diagnosed with endomyocardial biopsy at Nara Medical University Hospital between January 2007 and March 2021. They underwent coronary angiography and left ventriculography to exclude coronary artery and valvular diseases. Endomyocardial biopsy samples were obtained from a standardized location at the apical posterior wall of the left ventricle or the interventricular septum of the right ventricle. Among the 40 consecutive CA patients, 28 (70.0%) were diagnosed with ATTR-CM based on immunostaining, as described below, and were enrolled in this study. The remaining 12 patients had been diagnosed as CA other than ATTR-CM and were excluded from this study; one had Ig-κ AL cardiomyopathy (AL-CM), eight had Ig-λ AL-CM, and three had AA cardiomyopathy. In addition, an analysis of the The study protocols were approved by the Nara Medical University Ethics Committee  and followed the 1975 Declaration of Helsinki guidelines. Written informed consent for the approval of patient information analysis and publication was obtained from either the patient or his/her family members.−1.094 × age−0.287 (×0.739 for women). In evaluating the ECG, low QRS voltage was defined as an amplitude <0.5 mV in all limb leads. Poor R-wave progression in the precordial leads was defined as the loss or absence of R waves in V1-3. Atrial fibrillation included a history of paroxysmal atrial fibrillation and sustained atrial fibrillation. As for the parameters of TTE, LV ejection fraction (LVEF) was calculated via the modified Simpson method. Interventricular septum (IVS) thickness, posterior wall (PW) thickness, LV end-diastolic diameter (LVEDD), and LV end-systolic diameter were measured using M-mode. The early transmitral filling velocity (E) was measured using pulsed-wave Doppler. Using tissue Doppler imaging in the apical four-chamber view, the peak early diastolic velocity of the septal mitral annulus (e’) was measured, and the E/e’  ratio was calculated. Patterns of LV geometry were defined according to the American Society of Echocardiography recommendations [3 − LVEDD3] × 0.8 + 0.6 (g). LVM was normalized to body surface area (LVM index). Concentric LVH geometry was defined as an increased LVM index (>115 g/m2 in men and >95 g/m2 in women) with RWT > 0.42. Concentric LV remodeling geometry was defined as having a normal LVM index (≤115 g/m2 in men and ≤95 g/m2 in women) with RWT > 0.42. Eccentric LVH geometry was defined as an increased LVM index with RWT < 0.42.Clinical data, including electrocardiography (ECG) and transthoracic echocardiography (TTE) parameters, comorbidities, oral medications, and laboratory data, were obtained on admission. The estimated glomerular filtration rate (eGFR) was calculated according to the following equation for Japanese subjects : 194 × sndations . RelativEndomyocardial biopsy samples were fixed with 10% buffered formalin, embedded in paraffin, and sectioned at 4-µm thickness. Specimens were processed for hematoxylin-eosin (HE) and Masson’s trichrome (MT) stain. The cardiomyocyte diameter was measured at the nuclear level in at least 20 randomly selected cardiomyocytes from HE staining in a high-power field using a BZ-X710 microscope and BZ-X analyzer software system . CA was diagnosed based on the pathological information. When CA was suspected, based on HE and MT staining, we added Congo red stain. If Congo red was observed within the interstitial area, immunostaining to distinguish the amyloid subtype was performed using anti-TTR, immunoglobulin kappa (Igκ), immunoglobulin lambda (Igλ), and AA antibodies . A polyclonal antibody against a synthetic peptide corresponding to positions 115–124 of TTR (1:750 dilution) , and a mWe assessed the association between echocardiographic parameters and histological features obtained by TTR immunostaining in patients with ATTR-CM. To cover the entire myocardium area in the high-power field, multiple images were captured. These high-resolution images were jointed using the BZ-X analyzer software. The total myocardium area and the areas showing TTR were measured using TTR immunostaining with the BZ-X710 system . Endocarp < 0.05. JMP software  was used to analyze the data.Continuous variables were expressed as means and standard deviations or medians and interquartile ranges (IQR), as appropriate. Categorical variables were expressed as percentages. Spearman’s correlation test was used to determine the relationship between the two variables. Statistical significance was set at The baseline clinical characteristics of the 28 patients with ATTR-CM are presented in We analyzed the distribution of the LVM index and RWT among the 28 ATTR-CM patients by sex . Among tRepresentative general staining of endomyocardial biopsy specimens from patients with ATTR-CM is shown in The measurements of the degree of the area that was stained for TTR, the non-cardiomyocyte area, and the cardiomyocyte area were represented in p < 0.001), as shown in p = 0.03; p = 0.01; p = 0.06; The proportion of the area that was stained for TTR positively correlated with that of the non-cardiomyocyte area (p = 0.01)  B. The frThe present study of patients with ATTR-CM demonstrated the following significant novel findings: (1) 96.4% of patients had concentric LVH geometry; (2) enlargement of the non-cardiomyocyte area, with an increased amount of TTR amyloid deposition, was associated with LV diastolic dysfunction and LVH; (3) TTR amyloid deposition and enlargement of the non-cardiomyocyte area affected the amount of ROS accumulation in the cardiomyocytes; and (4) ROS accumulation correlated with LV systolic dysfunction.The clinical phenotypes of ATTR-CM include symmetrical wall thickening and progressive heart failure ,5,6. LV Furthermore, in this study, one patient with ATTRwt-CM with concentric LV remodeling geometry demonstrated a lower BNP level (32.6 pg/mL) without diuretic usage and better LV systolic and diastolic functions, compared to 27 patients with ATTR-CM with concentric LVH geometry, indicating that this patient might be in the early stage of disease development . Lai et The combination of TTR amyloid deposition and interstitial fibrosis contributes to the formation of non-cardiomyocyte areas , and TTRFurthermore, there is little understanding of the association between the pathological features and LV diastolic dysfunction in ATTR-CM. This study showed that enlargement of the non-cardiomyocyte area, but not cardiomyocyte hypertrophy, was associated with LVH. Our findings suggest that enlargement of the non-cardiomyocyte area together with an increased amount of TTR amyloid deposition might result in increased stiffness of the LV wall and consequent LV diastolic dysfunction in ATTR-CM hearts.2+ balance. Consequently, these cytotoxic responses may result in ROS accumulation and inflammation progression [In this study, using endomyocardial biopsy samples, we found that LV systolic dysfunction was associated with the extent of ROS accumulation in cardiomyocytes, but was not associated with TTR amyloid deposition or the non-cardiomyocyte area. In this study, the degree of TTR amyloid deposition and the non-cardiomyocyte area was positively associated with ROS accumulation in cardiomyocytes. Previous reports have demonstrated that mature TTR amyloid fibrils do not cause cellular damage, but TTR non-fibrillar aggregates are toxic to cardiomyocytes ,33,34,35gression ,39,40,41Additionally, it is well known that ROS accumulate by activation of neurohormonal systems, including the sympathetic nervous system and renin-angiotensin-aldosterone system ,43,44,45TTR amyloid deposition and subsequent enlargement of the non-cardiomyocyte area might contribute to LVH and LV diastolic dysfunction. ROS accumulation through the increase of TTR amyloid deposition and non-cardiomyocyte areas might be more sensitively related to LV systolic dysfunction. Based on our findings, the predicted mechanism of cardiac dysfunction in ATTR-CM hearts is shown in Stabilizing TTR homotetramers or reducing TTR production might preferably be applied early in the stage before TTR amyloid fibrils accumulate in the myocardium. This approach is necessary because the severity of TTR deposition was related to the extent of the non-cardiomyocyte area and was thought to affect cardiomyocyte damage. The fact that tafamidis, a stabilizer of the TTR homotetramer, was shown to have a better response in treating patients classified as New York Heart Association (NYHA) functional class I and II compared with those classified as NYHA class III supports this concept . Early dThis study has some limitations. First, the sample size was small and all samples were obtained from a single hospital. Second, the proportion of patients with ATTR-CM having concentric LVH geometry might be higher since endomyocardial biopsies might be mainly performed on patients with clinical symptoms in the advanced stage of the disease. Third, not all patients with ATTR-CM underwent genetic analysis. Fourthly, echocardiographic parameters of subclinical systolic dysfunction, such as global longitudinal strain, were measured in only four patients in this study. Given that most patients with ATTR-CM had preserved LVEF, further investigation using speckle tracking analysis is needed to elucidate the relation between the TTR deposition and cardiac dysfunction. Fifthly, the endomyocardial biopsy technique may have sampling errors in establishing a pathological diagnosis, although endomyocardial biopsy is reported to have a higher positive probability of detecting amyloid deposition than other methods, such as abdominal fat tissue biopsy in patients with ATTR-CM. A larger sample size should be evaluated to further clarify the mechanisms underlying ATTR-CM development.ATTR-CM mainly exhibited concentric LVH geometries. TTR amyloid deposition is associated with cardiac dysfunction via increasing the areas without cardiomyocytes and promoting ROS accumulation in cardiomyocytes.


Frontiers in Cardiovascular Medicine: Insights in General Cardiovascular Medicine: 2021, is to bring together excellent manuscripts of high-quality and high-citation potential, all of which gave been contributed by our editorial board members. Our criteria for selection include whether the topic addressed is focused on new discoveries and developments, current advances and challenges, as well as future prospects in the field of cardiovascular medicine research. This collection represents the quality and breadth of the papers published in this section, as well as the geographical variety of our scientific community. The rest of this editorial provides an overview of the articles included in the Insights in General Cardiovascular Medicine: 2021 collection .The Post-thrombotic Syndrome-Prevention and Treatment: VAS-European Independent Foundation in Angiology/Vascular Medicine Position Paper .– Post-thrombotic syndrome is a common and potentially risky complication of deep vein thrombosis that significantly affects patients' life quality. However, there are still great uncertainties in diagnosis, prevention, and treatment due to limited evidence-based approaches to clinical management. This position paper provided a practical framework and guidance for clinicians in PTS management.Diabetes and Its Cardiovascular Complications: Comprehensive Network and Systematic Analyses .– There is currently no cure for diabetes. This review highlights current advances in the study of diabetes mechanisms using multi-omics analytical approaches and recent findings on the relationship between diabetes and other biological processes. This review provides important information for the prediction, diagnosis, and treatment of diabetes that could be useful for both clinicians and researchers.EMbedding and Backscattered Scanning Electron Microscopy: A Detailed Protocol for the Whole-Specimen, High-Resolution Analysis of Cardiovascular Tissues .– Analysis of cardiovascular tissue ultrastructure is complex. The current commonly used study methods have limitations such as low resolution and low signal-to-noise ratio. This protocol developed a new experimental method and provided a novel approach for imaging cardiovascular pathophysiological processes.Identification of Novel Single-Nucleotide Variants With Potential of Mediating Malfunction of MicroRNA in Congenital Heart Disease .– Genetic mutation is the major cause of congenital heart defects (CHDs). This study identified miRNAs-mediated regulating on single-nucleotide variants from 3'-UTR of CHD-associated genes. This study suggests that miRNA-related gene regulation may be important but overlooked in the etiology of human congenital heart disease, suggesting that miRNA-related gene regulation should receive more attention in future CHD studies. The observations in this paper have important implications for clinicians.Screening for Asymptomatic Coronary Artery Disease via Exercise Stress Testing in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis .– This systematic meta-analysis studied the exercise stress testing (ETS) screen program for asymptomatic cardiovascular diseases in type 2 diabetes mellitus, demonstrating its moderate sensitivity and specificity in the initial screening. ETS is a very promising tool due to the advantages of being non-invasive, relatively inexpensive, easily available in most centers, and the fact that it involves no radiation. Further additional studies are warranted to address the detailed flow and timing of ETS.Relevance of Cor Pulmonale in COPD With and Without Pulmonary Hypertension: A Retrospective Cohort Study .– Pulmonary hypertension (PH), a complication of chronic obstructive pulmonary disease, is usually mild to moderate but can be severe in some patients. This paper suggests that cor pulmonale is associated with disease severity, providing recommendations for clinical researchers that cor pulmonale might be used to predict PH-COPD prognosis.Cognitive Impairment in Heart Failure: Landscape, Challenges, and Future Directions .– This review summarizes research advances in the screening, diagnosis, and management of cognitive impairment (CI) in patients with heart failure, as well as the latest preventive therapies. The prevalence of CI in heart failure patients adds a greater burden on the patients' poor prognosis and worsening life quality. This paper provides important directions for clinicians and researchers that future research addresses the knowledge gaps in the field forward CI in heart failure.Diagnostic and Therapeutic Management of the Thoracic Outlet Syndrome. Review of the Literature and Report of an Italian Experience .– This paper reviews the diagnostic, therapy, and management of Thoracic Outlet Syndrome (TOS). A report in Italy was also analyzed. It provides recommendations for clinical researchers in the treatment of TOS.Cardiorespiratory Responses During High-Intensity Interval Training Prescribed by Rating of Perceived Exertion in Patients After Myocardial Infarction Enrolled in Early Outpatient Cardiac Rehabilitation .– Exercise training is an effective strategy to improve cardiorespiratory and benefits the cardiovascular system , 2. ThisDetermination of Agrin and Related Proteins Levels as a Function of Age in Human Hearts .– A variety of strategies have been studied to promote endogenous proliferation of cardiomyocytes and promote cardiac injury repair , 4. ThisVascular Stem/Progenitor Cells in Vessel Injury and Repair .– This review summarizes the latest research progress on Vascular Stem/Progenitor Cells in vessel injury and repair. Stem/progenitor cells play an important role in the regeneration and recruitment of damaged vascular cells during vascular repair. This paper discusses potential future research directions for stem cell therapy and provides important ideas for researchers in this field.Rutaecarpine Inhibits Doxorubicin-Induced Oxidative Stress and Apoptosis by Activating AKT Signaling Pathway .– Rutaecarpine in doxorubicin-induced cardiotoxicity. This finding provides a new potential therapeutic option for the treatment of doxorubicin-induced cardiotoxicity.Cardiotoxicity is one of the main adverse reactions of doxorubicin in clinical cancer therapy applications , 6. ThisValosin Containing Protein as a Specific Biomarker for Predicting the Development of Acute Coronary Syndrome and Its Complication .– This paper analyzes human serum samples and found that serum valosin containing protein (VCP) levels could act as a biomarker to predict the development of acute coronary syndrome (ACS) and its complication, ventricular dysfunction. Biomarker identification is important for disease diagnosis and treatment. This study could provide important information for clinicians and researchers that VCP should be involved with the diagnosis and treatment of ACS.NAP1L5 Promotes Nucleolar Hypertrophy and Is Required for Translation Activation During Cardiomyocyte Hypertrophy .– Cardiac hypertrophy is a compensatory response of the heart to increased hemodynamic stress under various pressures, and if not relieved, it gradually develops into heart failure. This study showed the new role of Nap1l5 in translation control during the progression of cardiac hypertrophy. This paper provides a new potential therapeutic target for the treatment of cardiac hypertrophy and heart failure.Computed-Tomography as First-line Diagnostic Procedure in Patients With Out-of-Hospital Cardiac Arrest .– Coronary angiography is critical in patients with suspected causes of coronary arrest. This study reported that computed tomography scans can improve outcomes after out-of-hospital cardiac arrest (OHCA). This observation provides information for clinicians and investigators that CT should be routinely included in the diagnostic workup of OHCA regardless of the presence or absence of an ischemic ECG patterns.Association of Body Weight Variability With Progression of Coronary Artery Calcification in Patients With Predialysis Chronic Kidney Disease .– This paper explores the clinical significance of bodyweight variability (BWV) in patients with predialysis chronic kidney disease. It found that high BWV is independently associated with the progression of coronary artery calcification. This study provides important evidence of a high association between BWV and coronary artery calcification, and should be of concern to clinicians.Clinical Characteristics for the Improvement of Cushing's Syndrome Complicated With Cardiomyopathy After Treatment With a Literature Review .– Cushing's syndrome (CS) complicated with cardiomyopathy is a rare clinical type with high mortality. This study retrospectively reviewed case reports from literature and demonstrated that cortisol played an important role, and hypercortisolemia can improve significantly after remission. This is an interesting finding, but the detailed mechanism needs further study.Comparability of Heart Rate Turbulence Methodology: 15 Intervals Suffice to Calculate Turbulence Slope – A Methodological Analysis Using PhysioNet Data of 1074 Patients .– This study focused on common variations in the number of intervals after ventricular premature contraction (VPC) that are used to calculate turbulence slope (TS). Heart rate turbulence (HRT) is a characteristic heart rate pattern triggered by a VPC. This paper provides important information for clinicians that HRT occurred at early intervals after the VPC, whereas TS calculated from a later time interval reflected overall heart rate variability rather than differential responses to VPC.Left Ventricular Strains and Myocardial Work in Adolescents With Anorexia Nervosa .– Cardiovascular disease is a common complication of anorexia nervosa (AN). This study suggests that the cardiac function in AN patients was preserved. The paper outlines that global longitudinal strain was higher in AN patients, while the clinical significance required further investigation.A Novel Risk Score to Predict In-Hospital Mortality in Patients With Acute Myocardial Infarction: Results From a Prospective Observational Cohort .– This study developed a novel HAMIOT  risk score to predict in-hospital mortality of MI patients using 10 highly predictive variables. Using this tool, the risk score is easily calculated and the variables are easily obtained during hospitalization, offering a useful method for clinicians to predict the risk of mortality.Renal Denervation Attenuates Adverse Remodeling and Intramyocardial Inflammation in Acute Myocardial Infarction With Ischemia–Reperfusion Injury .– Acute myocardial infarction (AMI) is the most severe symptom of coronary artery disease and the leading cause of morbidity and mortality worldwide. This paper studied the protective effects on renal denervation (RDN) in myocardial ischemia/reperfusion (I/R) pigs. This data provides compelling evidence for the applicability and efficacy of RDN and suggests that this treatment strategy needs further development.JX, PL, PC, and MA are topic editors of this special issue and contributed to writing and revising of this editorial. LW, JL, and YL drafted the editorial. All authors contributed to the article and approved the submitted version.This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to JX), National Natural Science Foundation of China (82020108002 to JX), Innovation Program of Shanghai Municipal Education Commission (2017-01-07-00-09-E00042 to JX), the grant from Science and Technology Commission of Shanghai Municipality (21XD1421300 and 20DZ2255400 to JX), Natural Science Foundation of Shanghai (19ZR1474100 to LW), and the “Dawn” Program of Shanghai Education Commission (19SG34 to JX).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


While echocardiography is a versatile tool in the complex geometry of the Ebstein heart, it has limitations. CMR offers a total overview and has the advantage of reliable volume assessment of both ventricles. Comprehensive evaluation of pediatric patients with EA may therefore require a synergistic implementation of echocardiography and CMR.With the trend towards childhood surgery in patients with Ebstein anomaly (EA), thorough imaging is crucial for patient selection. This study aimed to assess biventricular function by echocardiography and cardiac magnetic resonance (CMR) and compare EA severity classifications. Twenty-three patients (8–17 years) underwent echocardiography and CMR. Echocardiographic parameters included tricuspid annular plane systolic excursions (TAPSE), fractional area change of the functional right ventricle (fRV-FAC), fRV free wall peak systolic myocardial velocity (fRVs’), and tricuspid regurgitation (TR). End-diastolic and end-systolic volume (EDV resp. ESV), fRV- and LV ejection fraction (EF) and TR were obtained by CMR. EA severity classifications included displacement index, Celermajer index and the total-right/left-volume index. Median fRV-FAC was 38% (IQR 33–42). TAPSE and fRVs’ were reduced in 39% and 75% of the patients, respectively. Echocardiographic TR was visually graded as mild, moderate, or severe in nine, six and eight patients, respectively. By CMR, median fRVEF was 49% (IQR 36–58) and TR was graded as mild, moderate, or severe in nine, twelve and two patients, respectively. In 70% of cases, fRV-EDV was higher than LV-EDV. LVEF was decreased in 17 cases (74%). There was excellent correlation between echocardiography-derived fRV-FAC and CMR-derived fRVEF (rho = 0.812, The online version contains supplementary material available at 10.1007/s00246-022-02948-3. The anatomical atrioventricular orifice is usually significantly enlarged . The traThis complex geometry causes challenges in the assessment of RA and RV function. Nonetheless, assessment of anatomical and functional parameters is important for prognosis and planning of potential surgical interventions , 6. TradEchocardiography is the most used modality for diagnosis and serial follow-up of patients with EA, as it is widely available by the bedside and applicable to every age, generally without the need for anesthesia. However, due to the generally severely enlarged fRA and fRV, it can be difficult to obtain good views, which limits reliable functional assessment. CMR has become a complementary and comprehensive tool for accurate and reproducible assessment of fRV function and tissue characterization in EA , 10. HowAs both imaging techniques have unique limitations and strengths, combining the modalities could be synergistic. The goal of the current study was threefold: (1) to assess biventricular function by echocardiography and CMR in young patients with EA; (2) to compare EA severity scores calculated by echocardiography and CMR; and (3) to compare imaging parameters with clinical markers of heart failure.In this cross-sectional multicenter study, all consecutive pediatric patients (aged 8–17 years) with EA who underwent routine clinical assessment in one of the five participating Dutch academic hospitals between May 2017 and March 2019 were included. Patients with univentricular palliation, excluding the RV from circulation, were excluded. Patients had a medical history taken and underwent physical examination, electrocardiogram, cardiopulmonary exercise testing, echocardiography, and CMR.In accordance with the ethical guidelines of the 1975 Declaration of Helsinki  the stud. Three to five subsequent heart beats were recorded.All participants underwent transthoracic echocardiography, and standard subxiphoid, left parasternal long- and short-axis, apical, suprasternal notch, and right parasternal views were acquired. All studies were supervised by a senior pediatric cardiology member of the research team. Each study was performed at rest on a locally available machineAll echocardiographic studies were analyzed in a single core lab by two cardiologists, L.G. performed the initial measurements and final values were obtained after consultation with L.K., an experienced cardiologist. The following echocardiographic parameters for assessment of biventricular dimensions and function were included: maximum peak flow velocities in both outflow tracts, the great arteries, and across the atrioventricular valves (Doppler E and A); maximal mitral and tricuspid annular plane systolic excursions on M-mode images ; fRV fractional area change (fRV-FAC); left ventricle (LV) ejection fraction (LVEF) by modified Simpson method; tissue Doppler peak systolic myocardial velocity (s′) of the fRV (fRVs’) and LV (LVs’) free wall (FW) and peak systolic longitudinal strain (peak systolic strain) of the LV in four-, three- and two-chamber views and peak systolic strain of the fRV FW. The severity of the tricuspid regurgitation (TR) was graded 0 (no regurgitation), 1 (mild), 2 (moderate) and 3 (severe), using the approach as recommended by the American Society of Echocardiography . These rReference values of both MAPSE and TAPSE and fRVs’ and LVs’ in children are age- dependent. Therefore, results were compared to age-matched reference values , 14. ValThe displacement index was measured in unrepaired patients with EA using the end-diastolic apical four-chamber view. The distance from the insertion of the anterior mitral valve leaflet to the displaced hinge point of the septal leaflet of the TV was measured Fig. A and indCMR was performed according to a standardized study protocol on locally available machines, all with 1.5-Tesla field strengths. Studies were performed by experienced technicians; no sedation was administered. All images were ECG-gated and obtained during breathhold. A multiphase, multislice volumetric data set was acquired using a fast 2-dimensional SSFP cine scan in short-axis orientation, covering the ventricles from base to apex. The following MRI acquisition parameters were used: TR 3.4, TE 1.4, flip angle 45°, and slice thickness 8 mm. Predefined FOV sizes were 36 × 36, with a matrix size of 224*192 for cine and 256 × 128 for phase-contrast (PC) flow. The number of reconstructed phases was limited to heart rate, with a minimum of 20 phases for SSFP and PC flow (median: 25). This data set was used to measure LV and fRV function. Standard four-, three- and two-chamber views with SSFP cine images were also obtained.CMR flow quantification was performed during breathhold, in the ascending aorta, the pulmonary trunk and the tricuspid valve, with 2D fast PC sequences. Standardized velocity-encoded (VENC) settings were defined, although technicians could alter settings to reduce aliasing. TE was minimized, with a flip angle of 20°. Flow in the outflow tracts was measured on a phase-contrast sequence in an imaging plane perpendicular to the arterial jet at 10 mm from the valve’s orifice.All CMR studies were analyzed in a single core lab by two radiologists, initial measurements were performed by W.E., and final values were defined after consulting J.H., an experienced cardiothoracic radiologist. The following CMR parameters for assessment of biventricular dimensions and function were included on cine images: end-diastolic volume (EDV) and end-systolic volume (ESV) of the fRV and LV; EF and stroke volume (SV) of the fRV and LV; LV peak systolic strain in four-, three- and two-chamber view, and global fRV peak systolic strain and fRV FW peak systolic strain in the four-chamber view. TR was determined using a stepwise approach. Flow measurements were analyzed in Qflow . Qflow measurements were used if deemed of adequate quality. Indirect calculation of the TV regurgitation fraction (TV-RF) was performed using the fRV-SV and pulmonary artery (PA) forward and backward flow volume, using the following equation: ; > 26%) .Volumetric data were derived after segmentation of the short-axis slices with QMass software . Trabeculae of the RV and LV were included in the volumes. Endocardial borders were manually traced. The aRV and fRV were defined according to Fratz et al.  Atrial vThe tricuspid annulus displacement index was calculated as by echocardiography. CI was calculated as previously described by Cieplucha et al.  as the r2-pulse) and maximal oxygen consumption (VO2max) were included as the percentage of predicted value (%Pred) for gender and age. The minute ventilation to carbon dioxide production slope (VE/VCO2 slope) was measured from the start of exercise until the respiratory compensation point.Exercise tests were performed on a bicycle ergometer in the patient’s own outpatient clinic. Breath-by-breath gas exchange analysis was performed continuously to measure the respiratory parameters. Heart rate and rhythm were continuously monitored using 12-lead electrocardiography. Blood pressure was measured every 2 min. Oxygen saturation was measured using pulse oximetry. Patients were encouraged to exercise to exhaustion. A peak respiratory exchange rate of 1.05 during testing was considered a maximally performed test. Each test consisted of three phases: (1) a 1-min resting phase; (2) a phase with gradual or stepwise increments of 10–15 W/min; and (3) a 3-min recovery phase. Peak workload, oxygen pulse (OR) were used, depending on normality of data. The CI grade and TR grade were compared using Cohen’s kappa. A Cohen’s kappa, R or rho value of ≥ 0.8 was classified as excellent, 0.60–0.79 as good, 0.40–0.59 as moderate, and < 0.40 as poor.Statistical analysis was performed using SPSS statistics version 25 . Data is presented as mean ± standard deviation (SD) or median and interquartile range (IQR), based on normality of data. Normality of data was verified using QQ-plots. For correlation of echocardiography- and CMR-derived parameters and clinical parameters, the Spearman rank (rho) or Pearson correlation coefficient (Twenty-three patients (8–17 years old) underwent both echocardiography and CMR Fig. . The demBy echocardiography, it was often difficult to obtain good images of the fRV FW due to the balloon-shape of the dilated RV. Especially in the four-chamber view, the rounded apical part often bulged out of plane. Although the median fRV-FAC was 38% 33–42) . Both global and FW fRV peak systolic strain were reduced with − 13.8% (− 10.3 to − 18.0) and − 17.7% (− 11.1 to − 26.2), respectively. TR was graded as mild, moderate or severe in nine, twelve and two patients, respectively. Enlargement of the fRV was seen in 52% of the patients. The fRV-EDV was higher than the LV-EDV in 16 out of 23 patients (70%). The median total right/left-volume index in unrepaired EA patients was 1.5 (IQR 1.3–2.5).p < 0.001) between fRV-FAC and fRVEF  and fRVs’  showed a non-significant, but inverse relation to fRVEF. Echocardiography-derived fRV FW peak systolic longitudinal strain showed no significant correlation to fRVEF , nor to other RV function parameters Although CMR-derived fRV global peak systolic strain had a moderate association with fRVEF , fRV FW peak systolic strain did not .Correlation between echocardiography- and CMR-derived parameters demonstrated an excellent correlation  cases. LVEF was (slightly) decreased in 17 cases (74%) and normal in the remaining cases. The median LV peak systolic longitudinal strain was reduced with − 18.8%. LV-EDV was reduced in seven (30%) patients.p = 0.015) between MAPSE and LVEF. There were no significant correlations between MAPSE and CMR-derived LV global peak systolic strain , as well as between CMR-derived LV global peak systolic longitudinal strain and LVEF . There was no correlation between echocardiography-derived LVs’ and CMR-derived LVEF either .Correlation between echocardiography- and CMR-derived parameters showed moderate correlation  between the displacement index measured by echocardiography  and CMR   . TR severity was graded lower by CMR compared to echocardiography in five patients, and higher in two patients .There was excellent correlation . There was no significant correlation between echocardiography- or CMR-derived functional parameters and results from cardiopulmonary exercise testing .Sixteen patients (70%) performed cardiopulmonary maximum exercise testing until exhaustion. There was good correlation between the echocardiography- or CMR-derived displacement index and the VE/VCOMost of the 23 patients (87%) were categorized as New York Heart Association (NYHA) functional class I, with only three patients being categorized as functional class II (13%). In the first patient with NYHA functional class II, higher EA severity scores were found, the TR was scored moderate to severe by echocardiography and the CMR-derived RVEF was severely reduced at 31%. The second and third patients with NYHA functional class II, however, showed low EA severity scores, less TR and the RVEF was within normal range. There were no significant differences between patients in NYHA functional class I or II regarding the obtained imaging parameters.2 slope.This study evaluates clinical use of echocardiography and CMR in young patients with EA. By echocardiography, it was often difficult to acquire images encompassing the entire fRV. Especially in four-chamber views, the rounded apical part often bulged out of plane. Left ventricular functional assessment by echocardiography was challenging as well, as the LV appeared rather compressed and less spherical, especially in the case of a severe displacement index and abnormal interventricular septal motion. By CMR, assessment of both fRV and LV volumes and function were feasible, while volumetric assessment was often suboptimal with echocardiography. Correlation between echocardiography-derived fRV-FAC and CMR-derived fRVEF was excellent, although echocardiography underestimates RV function. MAPSE and CMR-derived LVEF had moderate correlation. The correlation between echocardiography- and CMR-derived TR severity was only moderate, while correlation between the severity indices was excellent. Finally, there was a good correlation between the echocardiography- and CMR-derived displacement index and the VE/VCOIn general, CMR-derived fRVEF is considered the gold standard for functional assessment of the fRV. Nevertheless, implementation and serial follow-up with CMR can be challenging, especially in younger patients. Although it underestimates RV function, echocardiography-derived fRV-FAC showed good correlation with CMR-derived fRVEF. However, echocardiographic acquisition of proper fRV views can be difficult in patients with EA, and volumetric parameters were therefore not feasible with echocardiography. Alternative functional parameters, such as TAPSE and RVs’ are often used for qualitative assessment of fRV longitudinal function. TAPSE showed an inverse relation with fRVEF, contradictory to expected findings. It should be considered that TAPSE and RVs’ might overestimate functional RV performance, as the contribution of tricuspid annular movement to the functional RV may be decreased due to altered geometry in EA. CMR-derived fRV global peak systolic strain showed a significant association with fRVEF. It would be of great interest to further investigate if reduced fRV global peak systolic strain can predict deterioration of fRV function.Abnormal interventricular septal motion made LV assessment by echocardiography demanding. Below the hinge point of the TV septal leaflet, the septal wall showed leftward diastolic displacement, altering LV geometry and reducing cavity size. This was not counterbalanced by hyperactivity of the LV FW; MAPSE and LVs’ were reduced in 52% and 71% of patients, respectively.Grading TR severity by echocardiography is difficult. The current recommendations of the American Society of Echocardiography include jet characteristics, vena contracta width, hepatic venous backflow, and signal density of the regurgitation jet, but these are hardly applicable in patients with EA. Due to the anterior rotation of the functional TV annulus towards the RVOT, the TR jet cannot be fully appreciated in one single plane. Furthermore, the TR usually comprises a various number of jets originating from both coaptation defects and leaflet fenestrations, which limits accurate assessment of the jet and may result in underestimation of TR severity. The maximal TR jet velocity might be lower than expected due to the enlarged RA and decreased fRV function. Inferior caval vein enlargement or hepatic vein systolic flow reversal is seen infrequently because of the presence of the severely enlarged RA.TR quantification by CMR velocity mapping was also challenging, as only 35% of cases were deemed of adequate quality. Velocity mapping of the TR is hindered by the multiple directions of the regurgitation jets, which are difficult to encompass in one plane. Moreover, jets may change direction throughout the cardiac cycle because of systolic motion of the enlarged RV. The indirect quantification using velocity mapping of the pulmonary valve and fRV-SV, was feasible in all cases. Nevertheless, measurement is indirect and may suffer from difficulties in acquisition. In cases of suboptimal velocity-encoding parameters or incorrect positioning and/or angulation, flow characteristics will be misinterpreted. In future studies, 4D flow assessment of valves may offer a solution, providing datasets with multidimensional possibilities, especially in complex multidirectional flow patterns of the TV in EA . AlthougGrading EA severity has always been challenging. Several echocardiographic severity scores have been proposed, of which the Carpentier classification and the CI are the most used. The Carpentier classification, proposed in 1988 , incorpoBy CMR, the median right/left-volume index in patients with unrepaired EA was 1.5, with only six patients scoring > 2.5. Hösch et al.  were the2 slope. There were no other significant correlations between echocardiography- or CMR-derived parameters and results from cardiopulmonary exercise testing. This could be explained by the fact that the young EA population showed relatively good biventricular function and mild EA severity scores. Hypothetically, in patients with significantly reduced biventricular function and more severe EA, a better correlation with the functional status might be seen. This emphasizes the relevance of additional pediatric studies, in larger populations, to further explore the relations between imaging parameters, functional status, and other outcome measures.There was good correlation between the echocardiography- and CMR-derived displacement index and VE/VCOThis is the first combined echocardiography and CMR study to specifically target young EA patients (< 18 years old). The multicenter recruitment of consecutive patients, the broad age range and the fact that both surgical and non-surgical patients were included, introduces bias in the results. Moreover, clinical severity  was limited in the study population, impeding translation of results to more severe states of EA. However, including a wide spectrum of patients with EA over multiple academic centers improves the generalizability of our results in the general pediatric EA population. Although the sample size is relatively large for youngsters with EA, the number of patients limits extensive statistical analysis and decreases statistical power. Although an intra- and interobserver analysis could further elucidate the role of CMR and echocardiography in patients with EA, variability of implemented parameters was beyond the scope of this study. The complex anatomy of the RV causes continued debate on the optimal slice orientation for RV volumetric assessment with CMR. While an axial slice orientation might offer an alternative, short-axis image stacks are non-inferior to axial slices –28. ImagWith the approach of childhood surgery in patients with EA, thorough imaging has become crucial for patient selection. The complex geometry of the Ebstein heart hinders reliable echocardiographic assessment of biventricular dimensions and function. While severity scores are comparable between imaging techniques, reliable volumetric and functional assessment requires CMR Below is the link to the electronic supplementary material.