Cardiac hypertrophy is a distinguishing feature of some cardiovascular diseases. Our previous study showed that sodium ferulate (SF) alleviates myocardial hypertrophy induced by coarctation of the abdominal aorta, and these protective effects may be related to the inhibition of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) signaling pathways. This study investigated the inhibitory effect and mechanism of SF on myocardial hypertrophy in spontaneously hypertensive rats (SHRs). The effects of SF on cardiac hypertrophy were evaluated using echocardiographic measurement, pathological analysis, and detection of atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC) expression. To investigate the mechanisms underlying the anti-hypertrophic effects of SF, the calcium-sensing receptor (CaSR), calcineurin (CaN), nuclear factor of activated T cells 3 (NFAT3), zinc finger transcription factor 4 (GATA4), protein kinase C beta (PKC-β), Raf-1, extracellular signal-regulated kinase 1/2 (ERK 1/2), and mitogen-activated protein kinase phosphatase-1 (MKP-1) were detected by molecular biology techniques. Treatment with SF ameliorated myocardial hypertrophy in 26-week-old SHRs. In addition, it downregulated the levels of ANP, β-MHC, CaSR, CaN, NFAT3, phosphorylated GATA4 (p-GATA4), PKC-β, Raf-1, and p-ERK 1/2; and upregulated the levels of p-NFAT3 and MKP-1. These results suggest that the effects of SF on cardiac hypertrophy are related to regulation of the CaSR-mediated signaling pathway.As a common complication of many cardiovascular diseases, cardiac hypertrophy is characterized by increased cardiac cell volume, reorganization of the cytoskeleton, and the reactivation of fetal genes such as cardiac natriuretic peptide and  As an a (β-MHC) . Althoug (β-MHC) . Unfortuin vivo  is a member of the G-protein-coupled receptor C family and is expressed at multiple sites including the parathyroid, thyroid, kidney, bone, and gastrointestinal tract . CaSR inin vivo , and is in vivo . TherefoRadix Angelicae Sinensis and Lignsticum chuangxiong), and can be synthesized manually. SF is 3-methoxy-4-hydroxy-cinnamate sodium with multiple pharmacological effects such as anti-platelet, anti-oxidation, free radical scavenging, anti-inflammatory, and anti-thrombotic properties (Sodium ferulate (SF) is derived from ferulate acid extracted from Chinese herbal medicines  rats, 13 weeks old, and specific pathogen-free were provided by the Beijing Vital River Laboratory Animal Technology Co., Ltd. . To investigate the effects of SF, at 1 week after acclimatization, the SHRs were administered SF at 20 mg/kg/day (SF-20), 40 mg/kg/day (SF-40), or 80 mg/kg/day (SF-80); SHRs and age-matched male WKY rats as normal controls were given distilled water. The dosage of SF and the course of treatment were determined by clinical instruction and our preliminary experiment. Animals were intragastrically administered SF between 9:00 and 11:00 for 12 consecutive weeks. All animals were housed in specific pathogen-free animal facilities at Zunyi Medical University  with controlled light cycles (12 h light/12 h dark); food and drinking water were available The tail artery blood pressure of eight conscious rats was randomly monitored in each group weekly using the CODA Non-Invasive Blood Pressure System  once a week in a quiet, warm, and dark environment.Left ventricular structure and function index of the rats were measured with the Vevo2100 High Resolution Animal Ultrasound Imaging System  under anesthesia with pentobarbital sodium (30 mg/kg). The parameters included diastole of the left ventricular anterior wall  thickness, diastole of the left ventricular posterior wall  thickness, diastole of the left ventricular internal diameter , and average cardiac stroke volume (SV). To observe whether myocardial hypertrophy had been formed in 14-week-old SHRs, we randomly selected 4 rats in SHRs and WKY rats for cardiac ultrasound testing. After 12 weeks of SF administration, six SHRs and WKY rats were randomly selected in each group for cardiac ultrasound testing to observe the effect of SF.After 12 weeks of SF administration, the hearts of all rats were immediately removed under the anesthesia state and rinsed with cold phosphate-buffered saline. The left ventricular wall (including interventricular septum) and right ventricular wall were isolated and weighed after being blotted dry. As left ventricular hypertrophic parameters, the left ventricular hypertrophy index  and ratio of the left ventricular weight/right ventricular weight (LVW/RVW) were calculated.3) were randomly taken in each group to fix in 2.5% cold glutaraldehyde, washed in 0.1 mol/L phosphate buffer three times, fixed in 1% osmium tetroxide, dehydrated in an ethanol series, embedded in epoxy propane, polymerized in an oven at 70°C, sectioned into 70 nm slices, and finally examined under a transmission electron microscope .To observe the pathohistology of the myocardial samples, five rats were randomly selected in each group for Histologic analysis. The heart specimens were routinely fixed in 4% formaldehyde solution for 48 h and embedded in paraffin. Sections (3.5 μm thick) underwent hematoxylin and eosin (H&E) staining and Modified Masson’s trichrome staining for morphological analysis using the BX 43 Olympus Image Analysis System  . The degβ-MHC in the cardiac tissue, five rats were randomly selected in each group for Immunohistochemistry analysis. The paraffin-embedded sections (3.5 µm) were replaced in citrate buffer (pH 6.0) and boiled in a microwave on full power for antigen retrieval after deparaffinization. Thereafter, the slices were blocked in goat serum  for 30 min and then incubated separately with anti-ANP antibody  and anti-β-MHC antibody  at 4°C for 17 h. Subsequently, the sections were incubated with horseradish peroxidase-conjugated goat and anti-rabbit secondary antibodies for 20 min at 37°C, followed by visualization with a DAB Kit (Zsbio Commerce Store). The Olympus Image Analysis System (Olympus) was used for morphological analysis.To observe the protein levels of ANP and TMSYBR® Green Supermix (Bio-Rad) using the iCycler iQ Real-Time PCR Detection System (Bio-Rad). The amplification specificity was checked by the melting curve following the manufacturer’s instructions. The internal control gene was GAPDH. The primers were designed and synthesized by Sangon Biotech Co., Ltd. , and are shown in Five rats were randomly selected in each group for Gene expression analysis. Total RNA was extracted from cardiac tissues using TRIzol™ reagent  and the Reverse Transcriptase System  by the C1000 Touch™ Thermal Cycler . Quantitative PCR (qPCR) was conducted with the iQ® Tetra system (Bio-Rad), and transferred to polyvinylidene fluoride (0.45 μm) membranes  by Trans-Blot® Turbo™ Transfer system (Bio-Rad). The membranes were blocked in 5% defatted milk, followed by incubation with the following primary antibodies: anti-ANP polyclonal antibody , anti-β-MHC monoclonal antibody , anti-phosphorylated nuclear factor of activated T cells 3 (p-NFATc3) monoclonal antibody , anti-CaSR polyclonal antibody , anti-extracellular signal-regulated kinase 1/2 (ERK1/2) polyclonal antibody , anti-β-actin monoclonal antibody , anti-lamin B1 polyclonal antibody , anti-GAPDH polyclonal antibody , anti-NFATc3 monoclonal antibody , anti-p-ERK1/2 monoclonal antibody , anti-calcineurin (CaN) polyclonal antibody , anti-zinc finger transcription factor 4 (GATA4) polyclonal antibody , anti-p-GATA4 polyclonal antibody , anti-protein kinase C beta (PKC-β) monoclonal antibody , anti-Raf-1 polyclonal antibody , and anti-mitogen-activated protein kinase phosphatase-1 (MKP-1) polyclonal antibody . In some experiments, nuclear proteins were isolated from heart samples with the Nucleoprotein Extraction Kit . Samples were incubated with secondary antibodies (1:5000 dilution); GAPDH or lamin B1 (served for nuclear protein control) was used to normalize protein loading. Immunoassay and analysis were carried out using the Gel Imaging Analysis System with Quantity One 1-D Analysis Software v4.52 (Bio-Rad).Three rats were randomly selected in each group for Western blot analysis. The total protein of cardiac tissue samples was extracted using radioimmunoprecipitation assay (RIPA) lysis buffer supplemented with phenylmethyl sulfonylfluoride . The protein concentrations were detected by the BCA Protein Assay Kit . The protein samples were resolved on 6–12% gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis by the Mini-Proteanp < 0.05 were considered statistically significant. The differences between groups were analyzed by one-way analysis of variance. If the variance was homogeneous, the least significant difference method was used; if the variance was heterogeneous, Dunnett’s T3 test was used.All statistical analyses were performed using SPSS 18.0 software , and data are presented as the mean ± standard error of the mean (SEM). p < 0.05). However, SF caused the blood pressure of SHRs to decrease, especially at 80 mg/kg (p < 0.05).SHRs are a typical animal model of cardiac hypertrophy and hypertension. Their blood pressure increases gradually with age. To observe the effect of SF on blood pressure in SHRs, the tail artery blood pressure of conscious rats was monitored once a week. As shown in p < 0.05). After 12 weeks of administration, the left ventricular function was detected by ultrasound. Compared with WKY rats, LVAW; d and LVPW; d were increased and LVID; d and SV were reduced in 26-week-old SHRs (p < 0.05).As shown in old SHRs . SF-40 ap < 0.05). SF-40 and SF-80 significantly decreased the LVHI and LVW/RVW in SHRs (p < 0.05).Pressure overload leading to myocardial hypertrophy usually manifests as hypertrophy of the left ventricle—mainly increases in left ventricular weight. Thus, we evaluated the left ventricular weight of rats, and the results are shown in p < 0.05). Large amounts of blue-stained collagen fibers were deposited in the perivascular and myocardial interstitium of SHRs (p < 0.05). Transmission electron microscopy showed that the myofilaments of WKY rats were arranged in an orderly manner, the sarcomere band was clear, the mitochondria were abundant, and the Z-line was normal. However, myofilaments were dissolved, mitochondria were swollen and vacuolated, the tissue gap was large, and the Z-lines were fractured in SHRs .As markers of myocardial hypertrophy, ANP and  in SHRs . Immunohp < 0.05). At the same time, the level of p-NFAT3 protein in the cytoplasm was significantly downregulated in the myocardium of SHRs (p < 0.05). SF, especially 80 mg/kg, downregulated the levels of CaSR, CaN, NFAT3, and GATA4 in the left ventricular myocardial tissue of 26-week-old SHRs and upregulated the level of p-NFAT3 protein in the cytoplasm (p < 0.05).As shown in p < 0.05). SF, especially 80 mg/kg, significantly downregulated the levels of PKC-β, Raf-1, ERK1/2 and significantly upregulated the expression of MKP-1 in the left ventricular myocardial tissue of 26-week-old SHRs (p < 0.05; The levels of PKC-β, Raf-1, and ERK1/2 are significantly upregulated and MKP-1 expression was significantly downregulated in the myocardium of SHRs at the transcriptional and translational levels (β-MHC in SHRs. These findings clearly demonstrate that SF can alleviate myocardial hypertrophy in SHRs.Myocardial hypertrophy is a risk factor for human health and an independent risk factor for increased cardiovascular mortality . As an iβ-MHC were significantly upregulated in the myocardial tissue of SHRs. These results provide direct and indirect evidence of left ventricular hypertrophy caused by a continuous increase in blood pressure. As an antagonist of the endothelin receptor, SF has certain antihypertensive effects on SHRs. Meanwhile, SF significantly reduced the left ventricular wall thickness and left ventricular hypertrophy index, increased the left ventricular diameter and SV, improved myocardial pathological morphology and ultrastructure, and downregulated the levels of ANP and β-MHC in SHRs. Thus, SF inhibited the process of myocardial hypertrophy in SHRs, in part through its hypotensive effect. This is consistent with previous observations on the effect of SF on myocardial hypertrophy induced by abdominal aortic coarctation in rats.The blood pressure of SHRs increases continuously with age. Compared with age-matched WKY rats, the left ventricular wall thickness was significantly increased and the left ventricular diameter was significantly decreased in 14-week-old SHRs, indicative of the development of left ventricular hypertrophy. The left ventricular wall thickness increased, and the left ventricular diameter and SV decreased with the increase in age to 26-week-old SHRs, and LVHI and LVW/RVW, and the cross-sectional area of cardiomyocytes were significantly increased. These findings suggested that the left heart structure and function of 26-week-old SHRs were abnormal. Pathological cardiac hypertrophy is often accompanied by significant myocardial fibrosis . In thisp-GATA4 (p-GATA4 can initiate the expression of hypertrophy response genes such as ANP and β-MHC, which participate in the development of myocardial hypertrophy (β and its downstream signaling pathways play a regulatory role in the development of cardiac hypertrophy and heart failure (β can activate Raf-1 and the MAPK signaling cascade in the cytoplasm, which in turn mediates cardiac hypertrophy (β, Raf-1, p-ERK1/2, and upregulated the levels of p-NFAT3 and MKP-1 in the myocardium of SHRs. The results showed that the CaSR-mediated and PKC-MAPK signaling pathways were involved in the anti-hypertrophic effects of SF (The CaSR plays an important role in mediating pathological myocardial hypertrophy and in cardiovascular diseases such as myocardial ischemia-reperfusion injury, heart failure, and vascular calcification . CaSR isp-GATA4 . The p-Gertrophy . DAG canertrophy . The act failure . Moreoveertrophy . ERK1/2 ertrophy . ERK1/2 ertrophy . In thists of SF . These fts of SF . In a foIn summary, combined with our previous research, these results strongly demonstrate that SF can inhibit cardiac hypertrophy in rats through regulating the CaSR-mediated signal pathway and inhibiting the PKC-MAPK signaling pathways.


Parameters of left ventricular (LV) mechanics, obtained from speckle-tracking echocardiography (STE), were found to be of prognostic value in patients with heart failure and those who underwent cardiac surgery. This study aimed to assess the value of STE in patients scheduled to undergo surgical ventricular restoration (SVR).A total of 158 consecutive patients with baseline STE who underwent SVR due to an LV anteroapical aneurysm were included in the analysis. Preoperative longitudinal STE parameters were evaluated for their association with an outcome, defined as all-cause mortality, LV assist device implantation, or heart transplantation. The echocardiographic follow-up to assess the change in the regional function of the segments remote from the aneurysm was performed in 43 patients at a median of 10 months [interquartile range (IQR): 6–12.7 months] after SVR.During a median follow-up of 5.1 years (IQR: 1.6–8.7 years), events occurred in 68 patients (48%). Less impaired mean basal end-systolic longitudinal strain (BLS) with a cutoff value ≤ −10.1 % demonstrated a strong association with event-free survival, also in patients with an LV shape corresponding to an intermediate shape between aneurysmal and globally akinetic. Initially hypo- or akinetic basal segments with preoperative end-systolic strain ≤ −7.8% showed a greater improvement in wall motion at the short-term follow up.Patients with less impaired preoperative BLS exhibited a better event-free survival after SVR, also those with severe LV remodeling. The preserved preoperative segmental longitudinal strain was associated with a greater improvement in regional wall motion after SVR. BLS assessment may play a predictive role in patients with an LV anteroapical aneurysm who are scheduled to undergo SVR. The preserved longitudinal strain of basal LV segments is associated with an improvement in regional LV function after surgical ventricular restoration and with better event-free survival.Preoperative assessment of basal longitudinal strain can be used to predict the improvement in regional LV function and event-free survival of patients undergoing surgical ventricular restoration. Performing quantitative analysis of LV mechanics using two-dimensional speckle-tracking may become an important component of the integrative approach in SVR decision-making in these patients.Left ventricular (LV) remodeling after myocardial infarction leads to enlargement of the left ventricle, a change in its geometry, and an increase in wall tension, which continuously impairs the LV systolic function and clinically results in progression of heart failure (HF) . SurgicaTwo-dimensional speckle-tracking echocardiography (STE) is a useful technique for evaluating the regional and global LV function in patients with coronary artery disease. Global longitudinal strain (GLS) was found to play a predictive role in patients with HF  and in tThe aim of this study was to evaluate the value of preoperative longitudinal STE parameters in patients who underwent SVR due to an anteroapical LV aneurysm. We hypothesized that the regional function at the basal level of the left ventricle is a valuable factor in reverse remodeling after SVR and, therefore, may be of prognostic value for these patients.A total of 226 patients with a postischemic anteroapical LV aneurysm underwent SVR at our center between November 2007 and January 2019. In total, 158 of these patients had a preoperative transthoracic echocardiography suitable for speckle-tracking analysis and were included in this analysis (first patient in November 2007). The composite endpoint included all-cause death, LV assist device (LVAD) implantation, and heart transplantation. Mortality data were retrieved from the National Death Index; follow-up data from patients after heart transplantation and LVAD implantation were obtained from medical records and through telephone inquiries. No patients were lost to follow-up. The outcome analysis was conducted considering preoperative clinical and echocardiographic parameters, including STE parameters , mitral valve repair or replacement , or aortic valve replacement  was performed during the index procedure. The majority of patients underwent a modified Dor procedure without a patch ; the data were stored in the institutional data repository. All the images were analyzed retrospectively by a single investigator (ON) for the purpose of this study. LV end-diastolic and end-systolic volumes were measured in the apical 2- and 4-chamber views; EF was obtained using the modified biplane Simpson method . The assSpeckle-tracking analysis was performed using the EchoPac software version 201 . Longitudinal parameters of LV function were obtained for all the 158 patients from apical 2-, 3-, and 4-chamber views by manual tracking of the endocardial border at an average frame rate of 60 ± 11 fps. The longitudinal parameters were measured according to the current recommendations using the 18-segment LV segmentation model . MechaniThe short-term clinical and echocardiographic follow-up was available for 43 patients at a median of 10 months [interquartile range (IQR): 6–12.7 months] after SVR. At this time, data on the NYHA class were collected and 2D echocardiography with a quantification of LV volumes and EF was performed. The wall motion of basal LV segments with initial hypo- or akinesia was evaluated at the follow-up. The function of midventricular and apical segments was not compared, as the LV geometry changes after SVR and segments at the follow-up might not represent the same segments as at baseline. At the follow-up, STE with quantification of LV longitudinal parameters was performed in 27 patients.t-test or the Wilcoxon sign-rank test as appropriate, differences between qualitative variables with the chi-squared test, or the McNemar test as appropriate. The univariate and multivariate Cox proportional hazards regression analyses were applied to assess risk factors for the combined outcome in the total population. Due to the low number of events and the strong correlation between the echocardiographic parameters, it was not possible to run a comprehensive Cox regression model including several echocardiographic parameters. We evaluated individual echocardiographic parameters separately, adjusted for important clinical variables, by adding the respective echocardiographic variable to the baseline clinical model. Variables included in the model were selected on the basis of their clinical importance and their possibility to confound parameters of interest. The receiver operating characteristic (ROC) analysis with Youden's index was applied to determine the optimal cutoff values for predicting 5-year outcomes in the population that completed the 5-year follow-up. Furthermore, the Kaplan–Meier analysis was performed for the whole population to estimate the differences in event-free survival between the groups based on the obtained cutoff values, with a maximum observation period of 10 years. Interobserver variability of STE parameters was assessed for 20 randomly selected studies evaluated by two independent investigators (ON and YH) and expressed as interclass correlation coefficient (ICC) and coefficient of variation (CV). Statistical significance was defined as p < 0.05. The data were analyzed using SPSS, version 25 , and the Kaplan–Meier curves were created using Rstudio version 1.1.463 .All the variables are presented as mean (±SD) or median (with IQR), where applicable. Categorical variables are presented as numbers with percentages. Differences between continuous variables were assessed with the paired p < 0.0001 for all the types of strains); (2) mean peak strains throughout the cardiac cycle were greater (more negative) than mean systolic and end-systolic strains, with the difference being more pronounced for global strains than for basal strains ; (3) around 40% of all the LV segments and around 20% of the basal LV segments (p < 0.0001) had a PSS pattern with peak strain registered after aortic valve closure; (4) the mechanical dispersion of the basal LV segments was slightly lower than the mechanical dispersion of the entire left ventricle (p < 0.0001). These patterns were more prominent in patients with an aneurysmal LV shape and less prominent in patients with a globally akinetic LV shape . EF increased from a mean of 31.9 ± 10% to 39.3 ± 9.5% (p < 0.0001) (Predischarge postoperative echocardiography was performed in 71 patients at a median of 7 days (IQR: 4–14 days) after SVR and demonstrated a reduction in LV end-diastolic and end-systolic volume indexes by 31.8 ± 18.7% and 38.7 ± 19%, respectively, compared to the preoperative values ( 0.0001) .n = 43) are shown in The clinical characteristics of patients who had the short-term follow-up (p = 0.002). The global two-dimensional and STE parameters improved: LV volumes reduced and EF and global WMSI improved, systolic and end-systolic GLS improved (became more negative), and the proportion of LV segments with a PSS pattern decreased  or akinesia (n = 7), an improvement in the wall motion score of ≥1 at follow-up (hypokinesia to normokinesia or akinesia to hypo- or normokinesia) was observed in 29 initially hypokinetic segments (38.7%) and in 3 initially akinetic segments (42.8%). The ROC analysis to predict the improvement in segmental wall motion at the short-term follow-up was performed for various longitudinal strain parameters including the presence of a PSS pattern (p < 0.0001) (p < 0.0001). No significant difference in the PSS pattern was found in segments that had improved at the follow-up compared to those that did not improve. An example of improved LV mechanics at the 12 months follow-up is shown in Among the basal segments with preoperative hypokinesia ( pattern . End-sys 0.0001) . Segmentp = 0.5) and the Cox regression analysis . The era effect based on the release date of guidelines for the treatment of HF (p = 0.49).Eight patients died in the hospital within 30 days after the surgery. During a median follow-up period of 5.1 years (IQR: 1.6–8.7 years), 67 patients died (42.4%), 9 patients (5.7%) received an LVAD, and 2 patients underwent heart transplantation. The combined outcome  occurred in 68 patients (48%). Overall, the event-free survival rate at 1 year was 84.1% (95% CI: 77.5–89%), at 5 years 69.4% (95% CI: 61–76.4%), and at 10 years 48.3% (95% CI: 38–57.8%). The median event-free survival time was 9.5 years (95% CI: 7.6–11.4%). Overall, the 5-year survival rate was 72.1% (95% CI: 63.8–78.8%) and the 10-year survival rate was 49.3% (95% CI: 40–58.8%). There was no difference in event-free survival between men and women, as demonstrated by the Kaplan–Meier analysis , with a higher 5-year event-free survival rate in patients with BLS ≤ −10.1%  than in those with BLS >−10.1%   . The Kap1–47.8%) . Patient1–47.8%) . No signp < 0.0001; CV 6.6%) and BLS . A higher interobserver variability was found for segmental LV longitudinal strain .Excellent interobserver agreement was demonstrated for GLS  preserved preoperative segmental longitudinal strain was associated with a greater improvement in regional wall motion after SVR in segments remote from aneurysm; (2) patients with a less impaired preoperative longitudinal strain at the basal level of the left ventricle exhibited a better survival free from heart transplantation or LVAD implantation; (3) a less impaired BLS in patients with severe LV remodeling was associated with better event-free survival.In the post-STICH era, the indication for SVR has been challenged. A preoperative evaluation of LV remodeling is performed as a part of the workup, but prognostic markers to determine a favorable outcome are lacking. In this study, we assessed the value of using two-dimensional speckle-tracking parameters to assess the LV function and found an association with outcomes in patients who underwent SVR. Although previous studies have evaluated postoperative LV remodeling using STE , 27, to 2) was similar to that in patients in the RESTORE  study (80.4 ml/m2) and comparable to that in patients in the STICH trial (82 ml/m2). Moreover, in this study fewer patients underwent CABG (71.5%) than in the RESTORE study (95%) and the STICH trial (100%). Overall, the 5-year survival in this study (72.1%) was comparable to that of the RESTORE study (68.6%), the STICH trial, and other studies (The patients in this study had a higher mean EF 34 ± 9%) than the population that underwent SVR in the STICH study . Although according to multivariate model BLS did not demonstrate a stronger association with an outcome compared to FS and LV end-systolic diameter, this parameter is of prognostic value and might be useful in complex preoperative assessment of patients scheduled for SVR.As was shown in a subanalysis of the STICH trial, LV EF was not found to have predictive value for patients who underwent SVR. We believe that the function of LV regions remote from the aneurysm is a crucial factor for postoperative recovery. In this regard, involvement of basal LV segments in the scar is considered less favorable for SVR and such patients are often classified as not eligible for the procedure , 35, 36.This study shows the use of STE as a quantitative parameter of LV basal function that allows for objectively evaluating the residual LV myocardium. The assessment of LV basal myocardium is suggested by other research groups as a possible marker of LV functional improvement after SVR , althougThe use of STE parameters does not replace the conventional echocardiographic assessment of cardiac function and is not being proposed solely for the evaluation of patients scheduled for SVR. They should instead be considered in the complex assessment of patients' eligibility for the procedure and in the future might be implemented in an automated analysis of LV mechanics in a preoperative continuum.This study had a nonrandomized, single-center observational design, which is a known limitation of most outcome studies on SVR representing real-world data. At the time of data collection, STE was already the standard technique in our institution, and maximum effort was made to obtain high-quality studies that were suitable for the STE analysis.Surgical ventricular restoration was performed more than 10 years ago, which may have influenced the patient selection and the modification of treatment strategies, since HF medication and device therapy have changed significantly over the course of this study. However, the era effect did not show a significant association with an outcome. We also were not able to obtain data on medical treatments and device therapies in our patients at the time of follow-up. The short-term follow-up with an echocardiographic evaluation of LV remodeling was available only for a small number of patients, which is another potential source of bias.All the studies and STE analyses were performed using an echocardiography system from a single vendor; therefore the cutoff values for other vendors may differ. However, a recent comparison of various vendors did not reveal significant differences in LV longitudinal strain in patients with HF . The cutThis study demonstrated that STE parameters were associated with outcomes in patients undergoing SVR. We showed that patients with less impaired BLS, which reflects the regional function of the myocardium remote from the aneurysm, had a better survival free from LVAD implantation and heart transplantation, also in the presence of severe LV remodeling. Less impaired preoperative segmental longitudinal strain at the basal level of the left ventricle was associated with a greater improvement in wall motion at the short-term follow-up. The implementation of quantitative analysis of LV mechanics using two-dimensional speckle-tracking may become an important part of the integrative approach in decision-making for SVR. Furthermore, the results of this study might be used for the continuous development of automated computational analyses of LV function. Future studies should prospectively investigate the impact of STE.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of the Charité – Universitätsmedizin Berlin. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.All authors listed in the manuscript made a substantial contribution to this study reported in the manuscript. Each author was involved in the conception and design or analysis and interpretation of data, the drafting of the manuscript and its critical review for important intellectual content. All authors read the final version of the manuscript and approved its submission. The conception and design of the presented study were performed by ON, NS, MD, VF, and CK. Data collection was performed by ON, NS, MD, YH, JK, FH, and CK. The analysis and interpretation of data by all the co-authors. The statistical expertise by ON, JS, YH, and CK. The writing of the manuscript by ON, NS, and CK. The critical review and final approval of the article by all the co-authors.This study was supported by the DZHK (German Centre for Cardiovascular Research) and the BMBF (German Ministry of Education and Research).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.


Outcomes in the large and small PA lesion groups, rather than between PA lesion types, were compared at five threshold values for PA lesion sizes (2–6 mm with 1-mm increments) to streamline the results. The proportion of complete success was significantly higher in the large PA lesion group than in the small PA lesion group at the 5-mm threshold only. The proportion of absent success was significantly higher in the small PA lesion group than in the large PA lesion group at all thresholds. Univariate and multivariate analyses of the test cohort identified serum K as an independent predictive factor for the small PA lesion group, which was confirmed in the 105-case validation cohort. Chi-squared automatic interaction detector analysis revealed that the best threshold of serum K for predicting large PA lesions was 2.82 mEq/L. These results will be beneficial for treating PA in clinical settings because patients with low serum K levels and apparent adrenal masses on CT may be subjected to adrenalectomy even if the adrenal venous sampling test is unavailable.Primary aldosteronism (PA) is mainly clinically classified as unilateral aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism. Immunohistochemistry for aldosterone synthase reveals a diverse PA pathology, including pathological APA and aldosterone-producing cell clusters. The relationship between PA pathology and adrenalectomy outcomes was examined herein. Data from 219 unilaterally adrenalectomized PA cases were analyzed. Pathological analyses revealed diverse putative aldosterone-producing lesions. Postoperative biochemical outcomes in 114 cases (test cohort) were classified as complete success ( Primary aldosteronism (PA) is the most common cause of endocrine hypertension, which significantly increases cardiovascular complications due to autonomous aldosterone production . PA is dWe previously reported an immunohistochemistry protocol for aldosterone synthase (CYP11B2) that distinguishes CYP11B2 from a cortisol-synthesizing enzyme  . On hemaCYP11B2 immunohistochemistry also identifies subcapsular aldosterone-producing cell clusters  in most normal adult adrenal glands, which strongly express CYP11B2 . MoreoveIn recent years, increasing information has been gathered on the pathology and pathophysiology of PA; however, it remains unclear whether any relationship exists between PA pathology and unilateral adrenalectomy outcomes. Therefore, in this retrospective study, we attempted to elucidate the relationship between PA pathology and unilateral adrenalectomy outcomes, with a focus on the size of PA lesions and the preoperative predictive factor(s) of PA pathology, by generating the largest catalog of PA pathology and clinical data from 219 PA cases in 11 Japanese institutions.http://www.adrenal.jp/en) is a consortium of 28 Japanese institutions as of September 2018, which was registered in the University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] # 18756.This study was conducted as part of the multi-institutional JRAS study. JRAS (https://humandbs.biosciencedbc.jp/en/hum0185-v1-st1). Details of ethical approval and case selection are described in the Investigators in 11 JRAS-participating institutions acquired Institutional Review Board (IRB) approval and selected 242 cases from their own institutions  were performed by one of the authors (KN) ; the intensity of antihypertensives (see below and 2), plasma aldosterone concentration , plasma renin activity ; and adrenal venous sampling (AVS) data after intravenous stimulation using synthetic adrenocorticotropic hormone (ACTH). eGFR was calculated as follows: 194 × (serum creatinine level [mg/dL] − 1.094) × (age [years] − 0.287) × 0.739 ), respectively. Differences between two unpaired groups with normal and non-normal distributions were tested by the unpaired https://humandbs.biosciencedbc.jp/en/hum0185-v1-st1 [Supplementary Data 1]). CYP11B2 positivity was calculated using the Aperio Positive Pixel Count Algorithm as we previously reported , partial success [n = 19], absent success [n = 10]). Among these cases, the percentage of complete success was significantly higher in the large PA lesion group (80.5%) than in the small PA group (55.6%) only when the threshold was 5 mm  and absent success  between the large and small PA lesion groups at each of the five threshold values (2–6 mm with 1-mm increments). Among the 219 cases, postoperative biochemical outcomes were available in 114 (test cohort: complete success %) than in those who did not achieve success ; however, no significant difference was observed in CYP11B2 positivity between patients who achieved complete success and partial success  than in the small PA lesion group , and eGFR were not significantly different between the groups. The maximum tumor length measured on CT images (mm) was not significantly different between the groups; however, the large PA lesion group showed an enrichment of larger tumor lengths . This result presumably indicated that CT detected many non-functional adenomas ) than in the small PA lesion group . Preoperative serum K  was significantly higher in the small PA lesion group (mean ± S.D. = 3.61 ± 0.46 mEq/L) than in the large PA lesion group . Preoperatively, PAC was higher in the large PA lesion group than in the small PA lesion group, whereas PRA was not. Overall, the intensity of antihypertensives, LR, serum K, and PAC significantly differed preoperatively between the small and large PA lesion groups.To identify preoperative factors associated with the sizes of PA lesions, preoperative clinical data were compared between the large (≥5 mm) and small (<5 mm) PA lesion groups in the same test cohort n = 1, Table 2n = 112 [two cases were not included due to missing data], test cohort in Table n = 105, validation cohort in Table n = 218, Supplementary Table p < 0.001, Fig. To investigate whether a preoperative prediction model could be generated that differentiates between the small and large PA lesion groups, we used preoperative factors with significant differences in univariable analyses for multivariable logistic regression analysis . LR was removed from the analysis due to the lack of data in many patients. The results showed that serum K and PAC were independent predictive factors (https://humandbs.biosciencedbc.jp/en/hum0185-v1-st1) of heterogeneous PA pathology that allowed a simple classification of small and large PA lesions at a threshold of 5 mm, which correlated with postoperative biochemical outcomes but not clinical outcomes, and (ii) we demonstrated that cases with preoperative serum K levels <2.82 mEq/L had a markedly higher chance of having potentially unilateral, large PA lesions. These results will be beneficial for PA in clinical settings and the pathological diagnosis of PA lesions, particularly for cases with lower serum K levels and apparent tumor(s) on CT, because these tumor(s) must be APA rather than incidentaloma and may allow the patient to avoid invasive AVS.We herein retrospectively investigated the relationships between preoperative clinical data, pathological findings, and postoperative biochemical/clinical outcomes using a large sample from JRAS: (i) we generated the largest catalog . Clinical outcomes appear to be associated with the normalization of the aldosterone secretion status as well as systemic vascular damage due to PA and other disorders . The large PA lesion group in the present study had hypertension for a longer period, and prolonged hyperaldosteronism in these patients appeared to have diminished the effect of lesion removal on clinical outcome.The sizes of PA lesions were associated with postoperative biochemical outcomes but not clinical outcomes. These outcomes were recently defined by the Primary Aldosteronism Surgical Outcome (PASO) study using the Delphi method . The bioSeveral models for predicting unilateral or bilateral PA, the diagnosis of which was based on AVS but not on pathology, have been previously proposed –21. All As a follow-up to this retrospective study, we recently initiated a prospective study to collect additional data, including CT images analyzed by four independent radiologists, a pathological analysis of multiple parts of a resected adrenal gland, and the most reliable AVS method, superselective AVS [ssAVS] , 22, 23.In summary, we generated the largest catalog of heterogeneous PA pathology and demonstrated that pathological PA lesions or larger than or equal to 5 mm in size correlated with postoperative biochemical outcomes and that PA patients with serum K levels at or <2.8 mEq/L had a significantly higher chance of having APA than incidentaloma. Based on these results, we concluded that PA cases with serum K levels less than or equal to 2.82 mEq/L and with an apparent single adenoma on CT may undergo unilateral adrenalectomy even in the absence of AVS because the adenoma must be a large PA lesion .Supplementary Figure 1Supplementary Figure 2Supplementary Figure 3Supplementary Materials and MethodsSupplementary Table 1Supplementary Table 2Supplementary Table 3Supplementary Data 2


We aimed to quantitatively compare our iECG approach with invasive electro-anatomical mapping (EAM) during sinus rhythm with the objective of enabling functional substrate imaging and sudden cardiac death risk stratification in patients with cardiomyopathy. Thirteen patients  referred for endocardial and epicardial EAM underwent 67-electrode body surface potential mapping and CT imaging. The EDL-based iECG approach was improved by mimicking the effects of the His-Purkinje system on ventricular activation. EAM local activation timing (LAT) maps were compared with iECG-LAT maps using absolute differences and Pearson’s correlation coefficient, reported as mean ± standard deviation [95% confidence interval]. The correlation coefficient between iECG-LAT maps and EAM was 0.54 ± 0.19 [0.49–0.59] for epicardial activation, 0.50 ± 0.27 [0.41–0.58] for right ventricular endocardial activation and 0.44 ± 0.29 [0.32–0.56] for left ventricular endocardial activation. The absolute difference in timing between iECG maps and EAM was 17.4 ± 7.2 ms for epicardial maps, 19.5 ± 7.7 ms for right ventricular endocardial maps, 27.9 ± 8.7 ms for left ventricular endocardial maps. The absolute distance between right ventricular endocardial breakthrough sites was 30 ± 16 mm and 31 ± 17 mm for the left ventricle. The absolute distance for latest epicardial activation was median 12.8 [IQR: 2.9–29.3] mm. This first in-human quantitative comparison of iECG and invasive LAT-maps on both the endocardial and epicardial surface during sinus rhythm showed improved agreement, although with considerable absolute difference and moderate correlation coefficient. Non-invasive iECG requires further refinements to facilitate clinical implementation and risk stratification.This study presents a novel non-invasive equivalent dipole layer (EDL) based inverse electrocardiography ( With imopathies . TherefoPatients referred for endocardial and epicardial EAM and ablation were enrolled. Epicardial mapping was indicated because of either recurrent ventricular tachycardia with a suspected epicardial substrate or symptomatic premature ventricular complexes with a prior failed endocardial ablation. Anti-arrhythmic drugs, except amiodarone, were discontinued for a minimum of three half-lives prior to the ablation procedure. Amiodarone was continued because of its long half-life. The study protocol was approved by the local institutional review board . The study was conducted according to the declaration of Helsinki and all patients gave informed consent prior to non-invasive and invasive mapping.The workflow of the study is depicted in iECG procedure. Premature ventricular complexes and sinus rhythm complexes prior to premature ventricular complexes were excluded from analysis. The root mean square of all recorded signals was used to annotate QRS onset, J-point and T-wave end. One lead from the standard 12-lead ECG was used as timing reference to allow comparison of absolute timings between iECG estimations and invasive EAM timings.Baseline drift and 50 Hz noise were removed from the body surface potential map signals. Per patient, five subsequent sinus rhythm complexes were selected to be analyzed in the iECG method has been described in more detail in the iECG method simulates body surface potential maps using the patient specific EDL cardiac source model, the patient specific volume conductor model and the estimated ventricular activation sequence. Nine regions containing potential foci were localized: four at the left ventricular septum, two at the base of both the posterior and anterior papillary muscles of the left ventricle, two at the right ventricular septum and one at the insertion of the moderator band at the right ventricular free wall free wall . Unipolar and bipolar electrograms were simultaneously recorded with standard 12-lead ECG , and one of these leads was used as timing reference for electrograms. Post-procedure, bipolar and corresponding unipolar electrograms were manually reviewed by investigators who were blinded to the information from the corresponding iECG map. LAT was set at the maximal amplitude of the bipolar signal, corresponding to maximum downslope (dV/dt) in unipolar electrograms  were determined for the epicardium, right ventricular endocardium and left ventricular endocardium. Breakthrough of activation was defined as nodes with the lowest LAT value, and sites of latest activation were defined as the node with the highest LAT value. Euclidian distances between sites of earliest and latest activation were determined in millimeters (mm). Myocardial conduction velocity over surfaces was calculated as the minimum positive velocity between nodes, velocities more than 3 mm/ms were excluded. A relatively high cut-off of 3 mm/ms was used to account for velocities observed in regions with a high density of Purkinje-myocardial junctions as the conduction velocity of Purkinje fibers ranges between 2 and 3 mm/ms. This cut-off was used to take into account that the electrical pulse may spread via the Purkinje fibers to the neighboring myocardial tissue instead of via the myocardial tissue itself. Ventricular activation sequences were presented in right anterior oblique, left anterior oblique and inferior views . These anatomical coordinates were semi-automatically aligned to the CT-based ventricular anatomical model, according to anatomical landmarks .Data were presented as mean ± standard deviation or median [interquartile range], supplemented with 95% confidence interval (CI). Continuous data were compared using (un)paired Student’s n = 10) or symptomatic premature ventricular complexes (n = 3) were included. Patients were diagnosed with arrhythmogenic cardiomyopathy (n = 5), dilated cardiomyopathy (n = 2), symptomatic premature ventricular complexes (n = 3), or ventricular arrhythmias after healed myocarditis (n = 3). Patients had either sinus rhythm (n = 10) or atrial pacing by an implanted permanent pacemaker (n = 3) during body surface potential recording and the EAM procedure, see Thirteen patients  referred for epicardial and endocardial mapping and ablation of ventricular tachycardia (iECG procedure (correlation coefficient = 0.97 ± 0.02). The QRS morphology of the timing reference lead during EAM correlated with the timing reference lead of the recorded body surface potential map (correlation coefficient = 0.94 ± 0.02).The patient cardiac anatomical models had an inter-node spatial resolution of 8 ± 1 mm. The QRS complex morphology of the recorded body surface potential maps correlated with the QRS complex morphology of the simulated body surface potential maps in the Epicardial EAM was performed in all patients, right ventricular endocardial EAM in 10 patients and left ventricular endocardial EAM in four patients. EAM consisted of median 4611 [3369–5633] epicardial electrograms, 910 [280–1638] right ventricular endocardial electrograms and 605 [247–1412] left ventricular endocardial electrograms. The number of annotations per square mm was 20 ± 11 for the epicardium, 10 ± 5 for the right ventricular endocardium and 8 ± 4 for the left ventricular endocardium. The percentage of EAM per surface was on average 67 [range: 48–82]% of anatomical nodes for the epicardium, 45 [range: 15–79]% for the right ventricular endocardium and 48 [range: 22–71]% for the left ventricular endocardium. The anatomical EAM model was limited to the locations where the catheter had been positioned during the EAM procedure.iECG and EAM for LAT maps, and the comparison between earliest and latest activated nodes for both the epicardium and endocardium. The ranges between earliest and latest ventricular activation were not significantly different between iECG-LAT maps and EAM-LAT maps . The ranges of earliest and latest activation per patient are included in iECG and the EAM approach in a patient with a healed myocarditis with right bundle branch block. The fast and His-Purkinje mediated activation of the left ventricular myocardium is shown in contrast to the relatively slower activation of the right ventricle due to the right bundle branch block. iECG-LAT maps and EAM-LAT maps was 0.54 ± 0.19; [95% CI:  0.49–0.59] for epicardial maps, 0.50 ± 0.27; [95% CI: 0.41–0.58] for endocardial right ventricular maps and 0.44 ± 0.29; [95% CI: 0.32–0.56] for endocardial left ventricular maps , right ventricular endocardium  and left ventricular endocardium . iECG-LAT maps and EAM-LAT maps was not significantly affected by the absolute number of EAM electrograms (p = 0.324), the number of electrograms with abnormal voltage (p = 0.306) or the QRS duration (p = 0.485)  see . Howeverwere low . This maiECG-LAT maps and EAM-LAT maps: 3.3 ± 0.8 vs. 3.2 ± 0.9 for epicardial maps, 1.8 ± 0.6 vs. 2.1 ± 0.6 for right ventricular endocardial maps and 1.8 ± 0.5 vs. 1.8 ± 1.0 for left ventricular endocardial maps , right ventricular endocardium  or left ventricular endocardium .The number of endocardial breakthrough points was similar when comparing ial maps . These ftimation . Epicardial maps . The timiECG estimation of ventricular activation sequences during sinus rhythm with invasive high density endocardial and epicardial EAM in humans. Comparison of agreement between iECG-LAT maps with EAM-LAT maps showed moderate agreement. However, this observed agreement (correlation coefficient = 0.54 ± 0.19) was remarkably higher compared to a recent validation study (correlation coefficient = −0.04 ± 0.3) performed during sinus rhythm . However, we note that these conduction velocities are mostly determined by the velocity estimated at the surface of the myocardium. Consequently, in a Purkinje dense region, surface velocity may appear high because it also reflects the effect of the activation spread by the Purkinje fibers and not only by the myocardial tissue at the endocardial surface. Furthermore, at the epicardial surface, velocities may appear high due to the occurrence of transmural waves.The conduction velocities calculated on the epicardial and endocardial surfaces in this study for both the EAM-LAT maps and iECG method based on the observations of Durrer et al. and nine possible sites of early activation were localized  were based on a multi-focal search algorithm over the complete endocardium and epicardium, where the first identified focus was chosen based on the highest correlation between recorded and simulated body surface potentials . ConsequiECG accuracy (iECG and EAM-LAT maps. Both the epicardial and endocardial surfaces had an adequate spatial distribution of electrograms as reflected in the number of LAT per mm2 (see Post-processing of ECG signals, electrogram signals, and cardiac imaging influences accuracy . To achiaccuracy . However mm2 see . Further mm2 see .iECG approach for sinus rhythm, the technique requires further adaptations and refinements that will facilitate implementation in clinical practice. Further integration of cardiovascular imaging techniques may improve performance and spatial resolution (iECG procedure, allowing at maximum 3000 cardiac nodes, which directly affects the resolution of the cardiac anatomical model resulting in an inter-node spatial resolution of 8 ± 1mm. Diffuse or local myocardial fibrosis affects ventricular activation patterns in structurally diseased hearts. Integration of these structural abnormalities in the iECG method and refinement of the cardiac anatomical models is likely to improve imaging of electro-anatomical substrates (iECG may allow functional imaging of such 3-dimentional substrates in patients with arrhythmias or cardiomyopathy (iECG may play a role in the monitoring of disease progression and in sudden cardiac death risk stratification in patients with complex electroanatomical substrates, such as inherited cardiomyopathies. Eventually, reducing the number of electrodes of the body surface potential map that currently ranges from 67 to 256 electrodes, may improve clinical applicability (Despite a considerable improvement of the solution . Currentbstrates . Since emyopathy . Besidescability . For EDLcability . Mathemacability .This single center study with a small sample size included patients with structural heart disease, which may influence the generalizability of the results. Additionally, we used a set conduction velocity over the model to determine the initial estimation. This assumption may not hold in the presence of pathologies or myocardial scarring after prior ablation, but the EDL holds for homogeneous anisotropic tissue .iECG-LAT map. However, a possible influence of variations in heart rate, autonomic tonus or general anesthesia cannot be excluded. The quality of gold standard EAM may have been influenced by vendor specific algorithms within the EAM systems and regional mapping by the operator during the procedure. Inherent to invasive electrophysiological studies, EAM maps consisted of electrograms recorded from consecutive sinus rhythm complexes, whereas iECG maps were derived from five sinus rhythm complexes selected from the body surface potential map.Electro-anatomical mapping procedures and body surface potential maps were not simultaneously recorded, but in similar conditions especially concerning anti-arrhythmic drugs. During EAM, complexes were selected using dedicated Carto/Ensite EAM systems. Furthermore, sinus rhythm complexes directly following a premature ventricular complex were excluded for analysis in both the EAM and iECG during sinus rhythm in patients undergoing invasive endocardial and epicardial electro-anatomical mapping showed improved agreement when compared to prior validation studies, although with considerable absolute difference in both timing and breakthrough of ventricular activation. Non-invasive iECG of both the epicardium and endocardium may prove valuable as a diagnostic tool for functional imaging of electro-anatomical substrates in sinus rhythm where activation always starts at the endocardial surface, to improve the value of the ECG in screening for cardiomyopathy and sudden cardiac death risk stratification. Future research should focus on improving accuracy and spatial resolution before implementation into clinical practice to enable imaging of functional electro-anatomical substrates.Quantitative comparison of EDL-based The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by METC UMC Utrecht. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.RR, MB, JH, TO, FA, PD, and PL contributed to conception and design of the study. RB, WK, LB, RR, and MB organized the database. RR and MB performed the statistical analysis. RR wrote the first draft of the manuscript. RR, MB, PD, and PL wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.PD is owner of ECG Excellence BV. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In recent decades the number of adults with congenital heart diseases (ACHD) has increased significantly. This entails the need for scrupulous evaluation of the current condition of these patients. The ACHD population is one of the most challenging in contemporary medicine, especially as well-known scales such as the NYHA classification have very limited application. At the moment, there is a lack of universal parameters or scales on the basis of which we can easily capture the moment of deterioration of our ACHD patients' condition. Hence it is crucial to identify factors that are widely available, cheap and easy to use. There are studies showing more and more potential prognostic factors that may be of use in clinical practice: thorough assessment with echocardiography and magnetic resonance imaging , cardiopulmonary exercise testing  and biomarkers . Some of them are very promising, but more research is needed to create a specific panel on the basis of which we will be able to assess patients with specific congenital heart diseases. In recent decades the number of adults with congenital heart diseases (ACHD) has increased significantly, mostly due to substantial progress in pediatric cardiac surgery and cardiology . AccuratMore and more adult patients with CHD present advanced forms of heart failure (about 20–50% of this population) which is main cause of death in ACHD population, and their quantity will be growing . PatientThe purpose of this work is to review current prognostic factors in ACHD and their significance in the diagnosis of heart failure, prognosis and management of patients with CHD and accompanying HF.We searched the electronic database PUBMED (2000–2021). Additionally, data from international cardiovascular meetings and guidelines of cardiovascular societies were searched. The main data search terms were: adult congenital heart disease, echocardiography, magnetic resonance imaging, exercise, cardiopulmonary exercise testing, biomarker(s), marker(s), heart failure, NYHA class, prognosis, risk factor(s).2, total and active emptying fraction but especially length) were significantly associated with cardiovascular events  and ratio of right atrial to left atrial area (≥1.5) have also been reported as a bad prognostic factors in patients with Eisenmenger syndrome and pulmonary hypertension (The most basic parameter obtained in TTE is the systolic ventricular function (as expressed by an ejection fraction with the biplane Simpson's method), which is a well-established prognostic factor. Koyak et al. showed that moderately to severely impaired systemic ventricular function and moderate to severe subpulmonary ventricular dysfunction are predictors for sudden cardiac death (SCD) in the general CHD population . In adulr events . The autr events . Also, ir events  and tricr events . In postr events . Additior events , 15. In r events , 17. Mocortality . Therefortension , 17. Addrtension .n = 13) and a control group without (n = 26) histories of death and sustained ventricular tachycardia (VT), finding that left ventricle synchrony measured with CMR tissue tracking is associated with death and VT (n = 215), revealing that increased ventricular indexed end-diastolic volumes (>125 mL/body surface area) are not risk factors of elevated mortality or transplant (2 is associated with increased risk of adverse events in patients with a systemic right ventricle (2) calculated using MRI can be used as predictive factors of cardiac events in patients with biventricular heart after Fontan surgery  and systemic right ventricle , 19–23. h and VT . Rathod ansplant . Van derhout n =  historieentricle . A recen surgery . Results surgery , 29–34.  surgery .Cardiovascular computed tomography (CCT) is particularly useful in dissection, pulmonary embolism, and paravalvular abscess in the setting of endocarditis, where it may have advantages over echocardiography and CMR due to being less susceptible to prosthetic valve artifact. It is useful in assessment of coronary artery pathology and collaterals  Table 1Table 1.2), ventilatory efficiency [ventilation to carbon dioxide output (VE/VCO2) slope], chronotropic and blood pressure response, as well as exercise-induced arrhythmia and desaturation, improve the assessment of functional capacity and physical fitness and correlate well with morbidity and mortality in ACHD patients  and highest in TGA patients after an arterial switch operation, patients with various forms of valvular heart disease and repaired aortic coarctation   and double product at peak exercise (product of heart rate and systolic blood pressure). However, there was also high inconstancy in exercise capacity measured in various NYHA classes    (2 peak was able to predict prognosis (2 peak (2 in patients with a systemic right ventricle (2) to work rate (WR) relationship and ventilatory anaerobic threshold (VAT) to be notably reduced in the CHD population (lowest in univentricular heart population)  , which w ability . Predictoutcome)  and TGA f 78.8%) . Diller f 78.8%) . Especia (2 peak . Single entricle . Buys etulation) . This le2peak  is another simple test for quantification of exercise capacity; it relates to outcome in patients with pulmonary arterial hypertension , 3. Kemp2peak . Moreovek (2peak  54)..2peak (2r = 0.50)  and NT-proBNP . As a result, levels of GDF-15 corresponded with levels of NT-proBNP and values of VO2max—the highest mean GDF-15 was in groups of VO2max <65% and NT-proBNP >300 pg/mL, the lowest in groups of VO2max >85% and NT-proBNP <100 pg/mL . Additionally, level of GDF-15 higher than the reference value  was associated with NYHA class and decreased exercise capacity  and negatively with left ventricular ejection fraction  (p < 0.01)  and NT-proBNP has been presented by Eindhoven et al.  and Baggen et al. (r = 0.42). Elevated levels of hs-TnT (>14 ng/L) has also been observed in patients with systemic systolic dysfunction, non-sinus rhythm, second and higher NYHA class and especially systemic right ventricle or elevated pulmonary pressures (p < 0.05) and patients in NYHA class I (2.52 ± 1.6 ng/ml) compared to NYHA class II  as well as NYHA class III . Ang-2 was also elevated in patients with limited cardiopulmonary exercise. Additionally, elevated concentrations of Ang-2 were observed in patients with single ventricle physiology (11.21 ± 6.94 ng/ml) compared to those with a systemic left  or right ventricle , unlike NT-proBNP. Ang-2 is a promising biomarker, especially in the population of Fontan patients (p = 0.04) and III , as well as between NYHA class II and III (p = 0.02). Differences in NT-proBNP were also significant but not between NYHA class II and III.  and N-terminal-pro-BNP (NT-pro-BNP)] are best studied and especially useful in patients with biventricular circulation and less useful in patients with a Fontan circulation . Eindhov = 0.50) . In the 00 pg/mL . Eindhovcapacity . One stu < 0.01) . Interes < 0.01)  and was  < 0.01) . This wa < 0.01) . Thus, Gn et al.  (r = 0.4n et al.  (r = 0.4ressures . Baggen ressures . Hs-TnT ressures . Galectiressures . Angiopopatients . Ang-2 Tand III. . A singland III. .Some investigators have already tried to develop or apply existing scales and models of adverse outcomes risk prediction and poor exercise capacity to the population of CHD patients , 72–75. In ACHD patients any haemodynamic abnormalities, including arrhythmias, potentially causing heart failure that can be addressed by intervention or surgery must be excluded. The structural interventions not pharmacological treatment are the therapy of choice in this group of patients. There is the need for personalized risk assessment in ACHD involving not only signs of heart failure and/or arrhythmia but also accurate diagnosis of residual defects and possibilities of their interventional treatment and typing the best time for intervention. No ideal risk stratification scheme has so far been developed. The future perspectives regarding ACHD risk assessment should take into account arrhythmias monitoring, serial cardiopulmonary exercise testing for objective assessment of exercise intolerance, the serial assessment of biochemical biomarkers and perhaps in the future also genetic may be additional reasonable tool. Echocardiographic and other imaging markers needs personalization depending of the type of congenital heart defect .2, VE/VCO2, heart rate reserve. Due to the heterogeneity of this group of patients, relatively small amount of medical centers dealing with congenital heart diseases, lack of large multi-center studies and uneven access of medical centers to all presented factors, it is a very difficult task to create uniform rules for managing and monitoring the population of CHD patients.There is no possibility at the moment to assess and monitor ACHD with a single parameter or a simple scale that would apply to the whole population like the NYHA classification in heart failure patients. Patients with CHD are heterogeneous population and personalized assessment of patients' functional state is important not only for their diagnosis and management, but also for prognostic reasons. Considering all available diagnostic tools, selected CPET parameters, echocardiography and magnetic resonance imaging as well as NT-proBNP and GDF15 levels are valuable assessment tools of ACHD patients which provide the most information about patients and their prognosis. The most promising CPET parameters seem to be peak VOPL, MB, MM, and AB-D contributed to conception and design of the paper. PL and AB-D managed the literature research. PL wrote the first draft of the manuscript. MB, MM, and AB-D reviewed and made corrections to the manuscript. All authors contributed to manuscript final revision, read, and approved the submitted version.This project was financed by the Polish Mother's Memorial Hospital Research Institute.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.


Propionic acidemia is a rare genetic disorder of metabolism that predisposes patients to metabolic acidosis, lethargy, neurologic dysfunction, developmental delays, and cardiomyopathy. Perioperative anesthetic management is guided toward mitigating the effects of preoperative fasting times, maintaining normovolemia, and preventing cardiovascular complications secondary to underlying cardiomyopathy. Commonly used anesthetic agents may have undesirable side effects in these patients. Propofol, the lactate in Lactated Ringer's, and neuromuscular blocking agents that undergo ester hydrolysis are poorly metabolized and can lead to metabolic acidosis. Opioids, such as fentanyl and morphine, should be used judiciously in patients with coexisting developmental delays to avoid oversedation and delayed time to resuming oral intake postanesthesia. In addition, inhaled anesthetics have direct myocardial depressive effects and can compromise cardiac function in the setting of pre-existing cardiomyopathy. The perioperative period represents a critical time in this population and appropriate planning is crucial to prevent perioperative morbidity. We present a case of an eight-year-old child undergoing esophagogastroduodenoscopy under general anesthesia and describe the anesthetic concerns we addressed to provide a safe perioperative course. Propionic acidemia (PA) is a rare autosomal recessive disorder of metabolism and usually manifests shortly after birth with organic acidopathy, poor feeding, lethargy, vomiting, neurologic dysfunction, developmental delays, and cardiomyopathy . AnestheAn eight-year-old 22-kg child with a past medical history significant for PA, mild developmental delays, generalized hypotonia, dysphagia, and autism presented for EGD with biopsies to evaluate his eosinophilic esophagitis. An electrocardiogram performed prior to the procedure revealed normal sinus rhythm without any evidence of cardiomyopathy. He also had a recent echocardiogram that did not show any evidence of cardiomyopathy. His home treatment plan included a specific diet to control the intake of propiogenic substrates while ensuring normal protein synthesis. Labs revealed normal electrolytes (sodium 140 mmol/L and potassium 4.0 mmol/L) and glucose within a normal range (102 mg/dL).The patient was preadmitted to the hospital the day before the procedure for medical optimization. He was placed on an infusion of 10% dextrose and normal saline at 1.5 times the maintenance rate and an intravenous formulation of 450 mg of levocarnitine twice daily. The following day, the child was brought to the endoscopy suite after 10 hours of fasting. The dextrose infusion was continued throughout the perioperative period. Standard American Society of Anesthesiologists monitors were applied. Glucose was checked immediately prior to the induction of anesthesia and was a normal value. An inhalation induction was performed incrementally and carefully up to 8% sevoflurane and 100% oxygen. Fentanyl (50 μg) was administered intravenously to facilitate endotracheal intubation. Once endotracheal intubation was completed, the sevoflurane concentration was decreased to 1% to diminish any myocardial depressive effects of the inhaled agent. The EGD was completed in 30 minutes with no complications. The patient was extubated awake and transferred to the postanesthesia care unit. His recovery was uneventful and he was subsequently discharged home on the same day. The patient did not require further follow-up.PA is an autosomal recessive disorder with a prevalence of 1 in 100,000 live births, but it may be as high as 1:1,000 births in Greenlandic Inuits due to a prevalent mutation . MutatioPropionic acidemia can present in one of the following forms: severe neonatal-onset, intermittent late-onset, or a chronic progressive form. Neonatal-onset PA is characterized by poor feeding, hypotonia, metabolic acidosis, and lethargy in the first few days of life . Up to 3Primary management of PA includes a low protein diet and administration of levocarnitine. Levocarnitine is important because it conjugates with propionic acid to promote transfer out of the mitochondria and excretion into the urine . In addiAnesthetic goals for patients with PA aim to prevent acidosis and hypoglycemia to avoid end-organ dysfunction. Preoperative evaluation should include a cardiology consultation to evaluate cardiac function and thorough documentation of baseline neurologic status, including the presence of any developmental delays, hypotonia, or vision impairments due to optic neuropathy . FastingPropofol emulsions contain polyunsaturated fatty acids, which are metabolized to propionyl CoA and could increase the patient’s level of propionic acid, leading to acidemia . Due to For prolonged procedures, anesthetic intraoperative management should include adequate intravenous access to allow for concurrent administration of dextrose-containing fluids and fluid boluses as needed. An arterial line may be placed to measure electrolytes, acid-base status, ammonia, and lactate levels. Postoperatively, patients should be carefully observed for signs of deterioration. Axial hypotonia predisposes patients with PA to a weak cough, atelectasis, and pneumonia, so choosing an anesthetic regimen that avoids prolonged sedation is advisable .Patients with PA are at an increased risk of perioperative complications. Appropriate preoperative planning to avoid acidosis includes minimal fasting periods and administration of dextrose-containing fluid infusions. Cardiology consultation may be necessary to evaluate for cardiomyopathy and prolonged QTc interval. The commonly used anesthetic propofol is poorly metabolized and can worsen acidosis, especially when used as the mainstay anesthetic. Opioids should be dosed judiciously, with consideration for underlying developmental delays to avoid prolonged sedation and hospitalization. Patients with PA are also at risk for postoperative decompensation and a prolonged observation period in the recovery unit or overnight stay may be prudent.


As compared with NGT < 155, NGT ≥ 155 exhibited significantly worse insulin sensitivity and higher values of hs-CRP. No significant differences were observed between NGT ≥ 155 and IGT patients. There was a significant increase in 8-isoprostane (p < 0.0001) and Nox-2 (p < 0.0001), from the first to fourth group, indicating an increase in oxidative stress with the worsening of the metabolic status. Serum levels of 8-isoprostane and Nox-2 were significantly increased in NGT ≥ 155 compared to the NGT < 155 group, but similar to IGT. The global longitudinal strain (GLS) appeared progressively lower proceeding from the NGT < 155 to T2DM group (p < 0.0001). For similar values of left ventricular ejection fraction (LVEF), NGT ≥ 155 exhibited reduced GLS compared to NGT < 155 (p = 0.001), but similar to IGT patients. Our study demonstrated that NGT ≥ 155 subjects exhibit early functional impairment of myocardial contractile fibres, these alterations are correlated with increased oxidative stress. The aim of the present study was to evaluate the possible correlation between oxidative stress and subclinical myocardial damage, assessed with speckle tracking echocardiography (STE), in normal glucose tolerance (NGT) patients with one-hour plasma glucose values ≥ 155 mg/dL (NGT ≥ 155), comparing them to NGT < 155 subjects, impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) newly diagnosed patients. We enrolled 100 Caucasian patients. All subjects underwent OGTT. The serum values of oxidative stress markers (8-isoprostane and Nox-2) were assessed with an ELISA test. Echocardiographic recordings were performed using an E-95 Pro ultrasound system. We observed significant differences, among the four groups, for fasting plasma glucose ( In recent decades, many studies suggested that one-hour postload plasma glucose values ≥155 mg/dL (8.6 mmol/L), during an oral glucose tolerance test (OGTT), detects individuals at an increased risk of developing type 2 diabetes mellitus (T2DM) among those who have normal glucose tolerance (NGT) ; furtherNotably, also left ventricular (LV) diastolic function is significantly worse in NGT ≥ 155 in comparison with NGT < 155 and similar to IGT and T2DM subjects. These observations are clinically relevant and underline the correlation between early alteration of glucose tolerance and myocardial damage. To improve clinical prognosis, it is fundamental to recognize early morphological and functional cardiac alterations even before the appearance of clinically evident reductions in LV performance. In accordance with this, in the last two decades myocardial deformation evaluation represents one of the most important innovations in the echocardiographic field because it considers many parameters that provide information about myocardial function beyond standard echocardiographic indices . In particular, speckle tracking echocardiography (STE) is a second-level echocardiographic technique that allows semi-automatic quantification of myocardial global and regional deformation, for systolic and diastolic function, with an early detection of cardiac efficiency impairment . STE allIn addition, myocardial work (MW) is a new dynamic non-invasive method that takes into account myocardial deformation and blood pressure (BP) values, thus overcoming the load dependency of LV ejection fraction (LVEF) and LV strain . Global It is well known that in diabetic patients several pathophysiological factors, in particular metabolic abnormalities, inappropriate activation of the renin–angiotensin–aldosterone system (RAAS), and inflammation, may increase oxidative stress, which represents a common pathophysiological mechanism underlying CV diseases (CVD) and DCM . OxidatiIn accordance with this, chronic hyperglycaemia and insulin resistance (IR), which also characterize patients with NGT ≥ 155, by promoting mild chronic inflammation and oxidative stress, could play a predominant role in the association between higher one-hour postload plasma glucose levels and CV damage. In addition, it is conceivable that NGT ≥ 155 patients, characterized by a worse metabolic and inflammatory profile, show a greater oxidative stress than NGT < 155 similar to IGT and diabetic subjects. Therefore, it is a crucial issue to identify a possible association between increased oxidative stress and early myocardial alterations in order to understand the processes that lead to an increased CV risk before T2DM appearance. We designed this study to evaluate a possible correlation between oxidative stress validated markers (8-isoprostane and Nox-2) and myocardial deformation and efficiency parameters, obtained by STE, in NGT ≥ 155 patients, comparing them to NGT < 155 subjects, IGT, and newly diagnosed T2DM patients.We enrolled 100 newly diagnosed hypertensive Caucasian patients  participating in the Catanzaro Metabolic Risk Factors (CATAMERI) Study . All subThe ethics committee approved the protocol and informed written consent was obtained from all participants (code protocol number 2012.63). All of the investigations were performed in accordance with the principles of the Helsinki Declaration. Clinical BP measurements were obtained according to current guidelines. Readings of BP were obtained in the left arm of the supine patients, after 5 min of rest, using a standard sphygmomanometer. BP values were the average of three measurements after a 10 min period of rest in the supine position. This evaluation was repeated on three separate occasions at least 2 weeks apart. Patients with a clinic systolic BP (SBP) > 140 mmHg and/or diastolic BP (DBP) > 90 mmHg were defined as hypertensive . Pulse pAll laboratory measurements were performed after a fast of at least 12 h. A 75 g OGTT was performed with 0, 30, 60, 90, and 120 min sampling for plasma glucose and insulin. Glucose tolerance status was defined on the basis of OGTT using the World Health Organization (WHO) criteria. Plasma glucose was measured by the glucose oxidation method , and plasma insulin concentration was determined by a chemiluminescence-based assay (Roche Diagnostics). T2DM was defined according to the American Diabetes Association (ADA) criteria . Insulin sensitivity was evaluated using the Matsuda index (insulin sensitivity index [ISI]), calculated as follows: 10.000/square root of [fasting glucose (millimoles per liter) × fasting insulin (milliunits per liter)] × [mean glucose3meaninsulin during OGTT]. The Matsuda index is strongly related to euglycemic-hyperinsulinemic clamp, which represents the gold standard test for measuring insulin sensitivity . Triglycerides, total, LDL, and HDL cholesterol concentrations were measured by enzymatic methods . Values of estimated glomerular filtration rate (e-GFR) were calculated by using the equation proposed by investigators in the chronic kidney disease epidemiology (CKD-EPI) collaboration . Blood samples, obtained from fasted patients, were taken in tubes with separator gel and centrifuged at 4000 rpm for 15 min to obtain serum samples that were immediately stored at −80 °C.Quantitative determination of the 8-isoprostane  and Nox-2  was performed with commercial ELISA immunoassays according to the manufacturer’s instructions. Values of 8-isoprostane were expressed as pg/mL; the lower detection limit of the assay was 0.8 pg/mL. Values of Nox-2 were expressed as nmol/L, the lower detection limit of the assay was 0.25 nmol/L. The coefficient of variation (CV %) was <9%.Comprehensive 2D and Doppler echocardiography were performed using a commercially available ultrasound machine  and performed according to the American Society of Echocardiography (ASE) recommendations . EchocarLVM was calculated using the formula proposed by Devereux et al. and corrected for body surface area (BSA), to derive the LVM index (LVMI) . LV end-A 2D speckle tracking analysis was retrospectively performed using vendor-specific 2D speckle tracking software . Manual tracings of the endocardial border during end-systole in three apical views was performed to evaluate GLS.The transmural variation of the longitudinal strain across the myocardial wall was calculated under the assumption of linear distribution. The endocardial and epicardial strains were calculated exactly on the endocardial and epicardial region of interest (ROI) borderlines, respectively. Subsequently, the values of transmural , endocardial, and epicardial strain were obtained. The ratio of endocardial GLS to epicardial GLS was calculated using the endocardial GLS/Epicardial GLS (Endo/Epi) ratio for the assessment of the strain gradient (8). Additional indices of myocardial work were also calculated, in particular global constructive work (GCW) ; GWW ; and GWE (constructive work divided by the sum of constructive and wasted work) . Constructive work describes the net effect resulting from positive work (shortening) performed during systole and negative work (lengthening) performed during isovolumic relaxation. Wasted work describes the net effect resulting from negative work (lengthening) performed during systole plus positive work (shortening) during isovolumic relaxation. For the current analysis, LV segments with poor tracking or suboptimal image quality were excluded, as were subjects whose echocardiograms provided information on GLS and myocardial work in less than 17 segments. The software further provides a global work index  and the global work efficiency (GWE = GCW/(GCW + GWW)) . p <  0.05. All comparisons were performed using the statistical package SPSS 20.0 for Windows .Normally distributed data are reported as mean ± SD, and those not normally distributed as median and interquartile range. Variables having a positively skewed distribution were log transformed (lg10) before the correlational analysis. To test the differences among groups, analysis of variance (ANOVA) for clinical and biological data was performed, followed by the Bonferroni post hoc test for multiple comparisons. Chi-squared test was considered for categorical variables. Correlational analysis was carried out for the whole study population and according to different glucose tolerance groups. A linear correlation analysis was performed to compare GLS, GLS endo/epi ratio and GWE with different covariates including one-hour postload glucose, and oxidative stress biomarkers. Afterwards, variables achieving statistical significance were inserted in a multiple stepwise multivariate linear regression model to determine the independent predictor of GLS, GLS endo/epi ratio, and GWE. Data were considered significant at Among 100 patients evaluated by OGTT, 54 showed NGT, 28 IGT, and 18 have T2DM. Considering the cut-off point of 155 mg/dL for one-hour postload plasma glucose, NGT subjects were stratified into two groups: 30 with NGT < 155 (55.6%), and 24 with NGT ≥ 155 (44.4%). In There were no significant differences among groups regarding gender distribution and age. Anthropometric parameters, DBP, PP, heart rate (HR), total HDL and LDL cholesterol, and haemoglobin (Hb), were also not significantly different. From the first to the fourth group, there was a significant increase in SBP, triglyceride, and hs-CRP values as well as a reduction in e-GFR. p < 0.0001) and two-hour postload plasma glucose levels (p < 0.0001), as well as fasting (p < 0.0001), one-hour (p = 0.001) and two-hour (p < 0.0001) insulin values during OGTT significantly increased from the first to the fourth group. As expected, there was a worsening of insulin sensitivity accounting for the reduction in MATSUDA/ISI (p < 0.0001). Of interest, one-hour postload plasma glucose levels (p < 0.0001) and higher values of hs-CRP (p = 0.006), in comparison with NGT < 155, showing a metabolic and inflammatory profile similar to IGT individuals. Post hoc analysis by Bonferroni test confirmed that NGT ≥ 155 subjects have significantly worse insulin sensitivity as represented by a lower Matsuda index (p < 0.0001) and Nox-2 (p < 0.0001) serum levels, indicating a worsening in oxidative stress with the deterioration of metabolic status. In particular, 8-isoprostane (p < 0.0001) and Nox-2 (p < 0.0001) levels were significantly higher in the NGT ≥ 155 subjects compared to NGT < 155 group, without significant differences with IGT and diabetic patients.There was a significant increase, from the first to the fourth group, in 8-isoprostane (In p < 0.0001) and LVMI (p < 0.0001) in comparison with NGT < 155, NGT ≥ 155 and IGT. In particular, NGT ≥ 155 patients showed significantly higher values of diastolic interventricular septum (dIVS) (p = 0.009), diastolic posterior wall (dPW) (p = 0.01) and LVMI (p = 0.026) in comparison with NGT < 155, but similar to IGT. By contrast, NGT ≥ 155 group compared with T2DM group, exhibited significantly lower LVMI (p = 0.009), while no significant differences were detected between the two groups as regards dIVS and dPW. Regarding the left ventricular end-diastolic diameter (LVEDD), there were no statistically significant differences between the four groups.From the first to the fourth group there was a significant increase in LVMI; diabetic subjects exhibited a worsening in both LVM  (p < 0.0001), but similar to IGT. In addition, there was a progressive impairment in GLS endo values (p < 0.0001) and GLS endo/epi (p < 0.0001) proceeding from the NGT < 155 group to T2DM group. No differences were highlighted in GLS epi values among the four groups. From the first to the fourth group, there was a progressive worsening of left global systolic function evaluated as myocardial deformation and GLS ( 0.0001) . Furtherp < 0.0001) and a progressive increment in GWW (p < 0.0001). In detail, NGT ≥ 155 exhibited a worsening of GWE in comparison with NGT < 155 (p = 0.027), but similar to IGT and diabetic patients. Moreover, from the first to the fourth group there was a progressive reduction in GWE  (p < 0.0p = 0.006) in NGT ≥ 155 group compared to NGT < 155; this parameter was also decreased in diabetic patients compared to the remaining groups (p < 0.0001). Values of left pulmonary systolic pressure (s-PAP) were similar in NGT ≥ 155, IGT and T2DM groups, with significant lower values in NGT < 155 (p < 0.0001). Moreover, TAPSE/s-PAP ratio significantly decreased in T2DM group compared to NGT < 155 (p < 0.0001) and NGT≥155 (p = 0.025), remaining similar to IGT. In addition, a significant reduction in right systolic function was observed as demonstrated by lower values of TAPSE (p < 0.0001), but similar to IGT and T2DM patients. Finally, NGT≥155 had a significantly lower E/A ratio in comparison with NGT < 155  and different covariates . p = 0.002), Matsuda/ISI , and inversely correlated with one-hour glucose , 8-isoprostane , hs-CRP , Nox-2 , E/e’ , and LVMI . When GLS was considered as a dependent variable, in the whole study population it was significantly correlated with e-GFR , Matsuda/ISI , Hb , one-hour glucose , 8-isoprostane , hs-CRP , Nox-2 , E/e’ , and LVMI .GLS endo/epi ratio was significantly correlated with e-GFR , Matsuda/ISI , Hb , one-hour glucose , PP , 8-isoprostane , hs-CRP , Nox-2 , E/e’ , and LVMI . Subsequently, GWE was considered as a dependent variable and was significantly correlated with e-GFR  and Nox-2 added another 4.1%. Moreover, one-hour glucose was the major predictor of GLS explaining a 31.8% of its variation (p < 0.0001) and Matsuda/ISI added another 4.7% (p < 0.0001). Considering GWE as dependent variable, Matsuda/ISI was the main predictor justifying 24.6% (p < 0.0001) of its variation; Hb added another 7.8% and hs-CRP another 3.4%. When Matsuda/ISI was excluded from the model, hs-CRP resulted the major predictor of GWE variation justifying a 21.6% of its variation (p < 0.0001), one-hour glucose added a 7.3% (p < 0.0001) and Hb another 3.8% (p < 0.0001). The respective models justified a 35.4% for GLS endo/epi ratio, a 36.5% for GLS and 35.8% for GWE variation, respectively. Finally, variables achieving statistical significance were inserted in a stepwise multivariate linear regression model to determine the independent predictors of GLS endo/epi ratio, GLS, and GWE, respectively. In the whole study population, one-hour glucose was the major predictor of GLS endo/epi ratio explaining 31.3% of its variation  production and myocardial work efficiency . OxidatiAs demonstrated in a study conducted by Aasum et al., changes in cardiac metabolism appear early in the diabetic progression .2 lead to a reduced cardiac efficiency. Moreover, human studies confirmed that obesity is associated with alteration in myocardial substrate metabolism, structure and efficiency and that the addiction on myocardial fatty acid metabolism boost with the worsening of insulin resistance. Previous animal and human studies have demonstrated that obesity and T2DM are linked with increased myocardial O2 consumption (MVO2) and decreased cardiac efficiency . T2DM anIt is known that myocardial oxygen demand is the amount of oxygen that the heart requires to maintain optimal function and myocardial oxygen supply is the amount of the oxygen provided to heart by the blood . In our Our data stress the concept that NGT≥155 patients present a reduced myocardial efficiency and early functional alteration of myocardial contractile fibres, before LVEF reduction and clinically evident heart failure.The lack of progressive deterioration of endocardial strain may be explained by the relatively small sample size. We would like to emphasize that there was a consistent trend of LV layer-specific strain reduction from the endocardium to the epicardium, which is in agreement with previous studies that used layer-specific strain, demonstrating a myocardial gradient of strain, with a decreasing strain value from the endocardial to the epicardial layer in hypertensive and diabetic patients . In conclusion, the present study confirms the predictive role of one-hour postload plasma glucose values on metabolic and CV risk, highlighting the importance of performing OGTT, taking into account not only two-hour but also one-hour postload glucose levels to improve the stratification of CV risk.The novelty of our study is the demonstration of early functional alterations of myocardial contractile fibres in NGT ≥ 155 subjects, even before the reduction in LVEF; moreover, the impairment in myocardial performance was strongly correlated with increased oxidative stress. Therefore, it is important to reconsider the concept that NGT patients are at a low CV risk. The data obtained from our study not only confirm that NGT ≥ 155 subjects have metabolic and inflammatory profiles similar to IGT and diabetic patients, but also that they present cellular and subclinical organ damage as evidenced by increased levels of oxidative stress, and a reduction in global and multilayer strain and myocardial work efficiency. These data could play a central role in ongoing research on the association between early glycometabolic alterations and CV outcome.