Heart transplantation represents main therapy for end-stage heart failure. However, survival after transplantation is limited by development of graft rejection. Endomyocardial biopsy, an invasive and expensive procedure, is gold standard technique for diagnosis of rejection. Most of biopsy complications are observed using echocardiography. Novel echocardiographic techniques, such as myocardial strain and three-dimensional reconstruction, can be useful in heart transplant patients.To evaluate ventricular strain in heart transplant patients and association with rejection, cellular or humoral, as well as two- and three-dimensional echocardiographic parameters.p-value < 0.05.Cohort of patients from heart transplant program taken to echocardiography after endomyocardial biopsy, from December 2017 to January 2020. Ventricular strain and three-dimensional left ventricle parameters were studied. Rejection results were retrieved from medical record. Qualitative variables were expressed by absolute frequency and percentages, while continuous variables by means and standard deviations. Association between rejection and variables of interest was measured by odds ratio and confidence interval of 95%, with p = 0.118 and p = 0.227 for septum and free wall, respectively), humoral , or of any type (0.504 and 0.446). There was no correlation between rejection and left ventricle global longitudinal strain, three-dimensional ejection fraction or desynchrony index. Conventional parameters associated to rejection were left ventricle posterior wall thickness  and left ventricle mass index . Left ventricle posterior wall thickness remained significant after analysis of cellular and humoral rejection separately .123 post-endomyocardial biopsy echocardiographic exams were performed in 54 patients. Eighteen exams were excluded, lasting 105 exams to be evaluated for conventional and advanced echocardiographic parameters. Male patients were 60.4%. Prevalence of cellular rejection was 8.6%, humoral rejection 12.4%, and rejection of any type 20%. There was no association between right ventricular strain and rejection, whether cellular (There was no association between ventricular strain, three-dimensional left ventricular ejection fraction and the desynchrony index and rejection, cellular or humoral. Evidence of association of graft rejection with left ventricle posterior wall thickness and left ventricle mass index was observed. Heart transplantation (HT) represents the main therapy for end-stage heart failure, resulting in a survival rate of more than 90% one year after surgery . HoweverEchocardiography is currently the most useful non-invasive imaging modality for the evaluation and monitoring of transplant patients, as it is widely available, low-cost, safe and well tolerated. The recent development of novel echocardiographic techniques has increased the probability of early detection of graft dysfunction . In addiOther echocardiographic techniques such as speckle tracking, derived from the two-dimensional image, and potentially more accurate after three-dimensional reconstruction, enable assessment of myocardial deformation (strain) . SeveralA prospective cohort study was carried out with patients from the Cardiac Transplantation Program at Hospital Israelita Albert Einstein (HIAE) who underwent transplant surgery at the same institution. All transplant patients admitted in Cath Lab for EMB from December 2017 to January 2020 were selected. Adult HT patients (over 18 years old) who underwent transthoracic echocardiogram (TTE) within 6 h after EMB were included in the study. Individuals who had poor image quality were excluded.According to the HIAE protocol, HT patients underwent routine EMB, the first one usually performed on the seventh postoperative day (PO), when it is expected that the serum level of cyclosporine  reaches the reference value (350–450 ng/ mL). Then, EMBs are programmed to be held on the 14th PO and right before hospital discharge. Subsequently, EMBs are performed at day 45 of follow-up, 3, 6, and 12 months after transplantation. In addition to that schedule, other EMBs can be indicated depending on clinical manifestations, presence of infection or positive viral panel, each case individually evaluated. Each EMB was followed, within 6 h, by a TTE, as routine screening for procedure complications.The present study was carried out in accordance with the principles established by the Declaration of Helsinki, and its project approved by the Research Ethics Committee of HIAE. All patients had Informed Consent Term comprehensively read and signed, if agreed to participate. A copy of the term was attached to the patient's medical record. The research was conducted without cost or financial support to researchers or patients.All TTE were performed on an EPIQ 7  by one of the HIAE echocardiographers and recorded on optical media for further offline analysis of morphological and functional echocardiographic parameters by a single experienced echocardiographer (RCPLC), on an institutional workstation through the TOMTEC RV 4D software . Another EPIQ CVx device  was also used for offline calculation of LV automatic GLS (auto-strain) and LV three-dimensional measurements (3D ejection fraction and desynchrony index). All professionals involved in the acquisition of images, preparation of the echocardiographic report and offline analysis were unaware of the clinical characteristics of the patients, as well as the histopathological results.All two-dimensional echocardiographic measurements were obtained accordingly international validated guidelines . Except The assessment of right ventricular strain was performed using a 3D full-volume acquired with frame rate > 40 cycles-per-second and four-beat recording. Using the offline analysis software, the longitudinal alignment of the heart chambers in four- and two- chamber views was obtained, LV outflow tract diameter was measured, such as the distance between the mitral valve and the left ventricular apex and the distance between the tricuspid valve and the right ventricular apex, in addition to the RV basal diameter in short-axis acquisition and marking of the anterior and posterior cardinal points of the RV. After automatic detection of endocardial speckles and manual adjustments if needed, peak systolic strain of the RV free wall and septal wall were obtained. 3D volumetric and functional analysis of RV were also achieved, as well as RV dimensions, TAPSE and FAC.GLS was acquired through the analysis of its myocardial deformation obtained by four- two- and three-chamber views, after semi-automatic recognition of the endocardial borders and synchronization of the cardiac cycle.The 3D evaluation of the LV, similarly to the RV, was performed with a full volume acquisition, four-beat optimized, at least 40 frames-per-second, with the patient in expiratory apnea. After LV landing marks in systole and diastole were indicated, LVEF-3D was automatically obtained, as well as the 3D desynchrony index.EMBs were performed at the HIAE Cath Lab by an experienced interventional cardiologist. After venous femoral access, under radioscopic guidance, from 5 to 10 RV endomyocardial fragments were collected for subsequent histopathological analysis, performed by an experienced pathologist without knowledge of the echocardiographic results. Histological specimens were graded from 0 to 3R for cellular rejection according to international guidelines  and consp-values. Intra and interobserver variability was performed using the intraclass correlation index in a sample of 10 cases and considered excellent if >0.70. The analyzes were performed using the STATA/SE 15.1 software  and the significance level adopted was 5%.The results extracted from the database were evaluated, at first, regarding the presence or absence of rejection, whether cellular or antibody-mediated . Subsequently, the study was carried out by evaluating data segmented per type of rejection. Qualitative variables were described by number and percentages and quantitative variables were described by mean ± standard deviation, once the properties referring to the assumption of normality of the data were satisfied. The investigation of the variables of interest in the exams in relation to cellular rejection, humoral rejection by immunofluorescence or immunohistochemistry and rejection of any type was carried out using models of equations of generalized estimation with binomial distribution and interchangeable correlation structure, seeking to contemplate the dependence between the measurements of different exams of the same individual. The results were presented by odds ratio (OR), confidence intervals of 95% (95% CI) and From December 2017 to January 2020, 123 post-EMB echocardiographic examinations were performed in 54 HT patients at the institution. Of these tests performed, 18 were excluded because they had poor quality images. The 105 remaining exams corresponded to 48 patients, 29 were men (60.4%) and 19 were women (39.6%). The number of exams per patient ranged from one to six, as follows: one exam in 21 patients (43.8%), two exams in 11 patients (22.9%), three exams in 6 patients (12.5%), four exams in 7 patients (14.6%), five exams in 2 patients (4.2%) and six exams in one patient (2.1%) .2 and the mean body mass index (BMI) was 24.1 Kg/m2 ranging from 17.7 to 34.2 Kg/m2  in the population studied. The demographic characteristics of the patients were described in relation to the moment of the first examination. The mean age at the time of the examination was 50 years, ranging from 18 to 72 years. The weight varied between 43 and 93 Kg, with an approximate average of 68 Kg. The mean body surface area (BSA) was 1.77 m.2 Kg/m2 .p = 0.005] and the left ventricular mass index (LVMI)  significantly differentiated in the exams with rejection from those without. The other parameters did not show significant differences. Thus, it can be said that when LVPW increases 1 mm, the chance of rejection increases 66% and when LVMI increases 1 g/m2, the chance of rejection increases 2.7%.According to p-value lower than 0.20. Thus, a multivariate model was obtained with the following variables: LV diastolic diameter (LVDD), interventricular septum (IVS) and LVPW thickness, LVMI and the presence of pulmonary hypertension (PH). Based on this adjustment, we found that LVDD, IVS and IMVE were not significant , while LVPW and PH were independently associated with rejection (p < 0.05). When the LVPW increases 1 mm, the chance of rejection increases 1.685 times ; the chance of rejection among patients with PH is 2.252 times that observed among patients who do not have PH .Also based on the results of p = 0.042]. We also verified that E/e' was significantly associated with rejection .Results obtained by Doppler are shown in p = 0.001], RV stroke volume (RVSV) , right ventricular internal diameter, measured at tricuspid level (RVID2) , and RV longitudinal diameter (RVID3)  were significantly different between patients with and without rejection. However, no multivariate model was possible since those variables are highly correlated with each other.Quantitative variables obtained by offline 3D analysis regarding rejection are described in p = 0.085].RV strain results did not differentiate patients with rejection from those without  . ResultsRegarding the type of graft rejection, we observed a moderate or severe cellular reaction in 9 cases (8.6%) . Antibodp = 0.021; and OR 1.033 , p = 0.008, respectively]. No Doppler-derived echocardiographic parameter was significantly associated to cellular rejection.Prevalence of cellular rejection was 8.6%  in our sample, and their echocardiographic parameters and association with cellular rejection are shown in p = 0.009], RVSV , RVEF  and RVID3  significantly differentiated exams with cellular rejection from those without. Results from RV analysis are shown in p = 0.019) and when RVEF increases 1%, chance of cellular rejection increases 5.4% . No associations were observed between RV strain and cellular rejection , ejection , as wellp = 0,038] and the presence of PH  were significantly associated to humoral rejection. A marginally significant result of association between pericardial effusion and humoral rejection was observed . Other findings are shown in p = 0.047), and chance of humoral rejection among patients with PH is 2.85 times higher than those without .Prevalence of antibody-mediated  rejection was 12.4%  in the studied population. We observed that only LVPW  and E/e'  ratios were significantly associated to humoral rejection. A multivariate adjustment was performed and only E/e' ratio was associated to humoral rejection (p = 0.005).When it comes to Doppler-derived echocardiographic parameters and their association with humoral rejection, we observed that E/A . We also observed that either RV strain variables , ariables  or 3D evariables  did not The results of our research showed no association between RV and LV myocardial deformation and graft rejection in heart transplant patients. Although the observations found are different from the initial expectation regarding the importance of right ventricular strain in cases of cardiac graft rejection, the present study was a pioneer in the classification of the type of rejection after HT and its correlation with the echocardiographic findings derived from the ST. Most of the studies found in literature that deal with rejection after HT use cellular type as an outcome. Studies with advanced echocardiography in post-HT patients have also been published, although they do not specify which type of rejection is more prevalent. Our series reveals, based on the differentiation of the type of rejection, a higher prevalence of antibody-mediated rejection. To date, we are not aware of other studies that address this rejection classification, which highlights the relevance and originality of our research.According to the findings of Cruz et al. , the myoA study with heart transplant patients published by Marciniak et al. , using TThe present work, in its analysis of the left ventricular GLS, found no evidence of association between the results obtained with this technology and the presence of graft rejection, whether cellular or humoral. Ambardekar et al.  failed tThe role played by GLS in HT patients who develops graft rejection can be amplified by adding circumferential deformation in the equation. Global circumferential strain (GCS) of those patients who develops antibody-mediated rejection, according to Ciarka et al. , show a p = 0.001) and RVSV (p < 0.001), derived from three-dimensional analysis, with graft rejection, demonstrating the relevance of right ventricular assessment in the identification of cellular rejection. D'Andrea et al.  and LVMI (p = 0.001) with the presence of rejection of any type. Splitting rejection events into subtypes, we observed that these same parameters still have statistical relevance in the association with cellular reaction . In the specific evaluation of humoral rejection results, an association was observed with posterior wall thickness (p = 0.038) and with the presence of HP (p = 0.026), with a borderline significant p-value for pericardial effusion. In 2009, Estep et al. , which denotes some damage to the diastolic function of those patients with positive biopsies. These findings corroborate what Mena et al.  that had inadequate echocardiographic view for acquiring satisfactory images for analysis were excluded. As described by Bacal et al. , that fiRecently, Carrion et al.  evaluateMost studies in the literature with a HT population present inference related to general rejection or just the cellular type. Despite this, in 2004, Subherwal et al.  . Graded Another data capable of impacting the results of the HT is the time of cold ischemia of the graft, directly related to the logistics described and documented in the 3rd. Brazilian Guideline on Heart Transplantation . PickeriRegarding the association of antibody-mediated  rejection, recent developments in diagnostic quantification methods cannot yet be translated into the volume of publications. In 2009, Tan et al.  describeWe consider limitations of the present study the fact that it conducted in a single HT reference center, with a non-uniform operative technique. Data that could influence the appearance of rejection, such as ischemia time and previous heart disease and comorbidities, were not studied. The small number of rejection cases within our sample can also be considered a limiting factor to the reproducibility of the present study. The presence of laboratory results, such as measurement of C-reactive protein, troponin and atrial natriuretic peptide, concomitant with histopathological findings, could add scientific value to the found observations. Certainly, more studies related to the echocardiographic evaluation of heart transplant patients should be conducted, in order to scientifically support the investment in a non-invasive method of early identification of rejection. With the promising results of the technology currently available, it is possible to reduce the burden of EMB, both in terms of the risks of the procedure itself and the resources provided for its performance, aiming primarily at the benefit of the heart transplant patient.The authors concluded that some conventional echocardiographic parameters, such as LVPW thickness and LV mass index, appears to be significantly associated to rejection after heart transplantation. In addition, assessment of diastolic function has an important role in rejection, as shown by E/A and E/e' ratios. When it comes to antibody-mediated type of rejection, LVPW thickness and presence of pulmonary hypertension were significantly related to positive results after endomyocardial biopsy. We did not observe strong association of advanced echocardiographic parameters, as longitudinal strain from both ventricles or 3D variables, and rejection of any type in our sample.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 Comitê de Ética em Pesquisa do Hospital Israelita Albert Einstein. The patients/participants provided their written informed consent to participate in this study.RC, SM, AR, CM, FB, and MV contributed for the concept and design of the study. RC, CF, EF, and AR collected and organized the database. AC performed endomyocardial biopsies. RC and CF were responsible for data analysis and drafting. SM, AR, and MV reviewed manuscript sections. All authors read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The severity of cardiac impairment in acute heart failure (AHF) predicts outcome, but challenges remain to identify prognostically important non-invasive parameters of cardiac function. Left ventricular ejection fraction (LVEF) is relevant, but only in those with reduced LV systolic function. We aimed to assess the standard and advanced parameters of left and right ventricular (RV) function from echocardiography in predicting long-term outcomes in AHF.via ROC analysis. For the RV, these were the tricuspid annular plane systolic excursion, RV fractional area change, tissue Doppler imaging (TDI) peak tricuspid annular systolic wave velocity, both peak- and end-systolic RV free wall global longitudinal strain (RV GLS) and strain rate (mean RV GLSR), RV ejection fraction (RVEF) derived from a 2D ellipsoid model and the ratio of the TAPSE to systolic pulmonary artery pressure (SPAP). For the LV, these were the LVEF, mitral regurgitant ΔP/Δt (MR dP/dt), the lateral mitral annular TDI peak systolic wave velocity, LV GLS, and the LV GLSR.A total of 418 consecutive AHF patients presenting over 12 months were prospectively recruited and underwent bedside echocardiography within 24 h of recruitment. We retrospectively assessed 8 RV and 5 LV echo parameters of the cardiac systolic function to predict 2-year mortality, using both guideline-directed and study-specific cutoffs, based on the maximum Youden indices –1 mean RV GLSR was associated with worse outcome compared to > −1.8 s–1 [HR 2.13 95% CI 1.33–3.40 (p = 0.002)]. TAPSE:SPAP of > 0.027 cm/mmHg (vs. < 0.027 cm/mmHg) predicted worse outcome [HR 2.12 95% CI 1.53–2.92 (p < 0.001)]. A 3-way comparison of 2-year mortality by LVEF from the European Society of Cardiology (ESC) guideline criteria of LVEF > 50, 41–49, and < 40% was not prognostic [38.6% vs. 30.9 vs. 43.9% (p = 0.10)]. Of the 5 parameters of LV systolic function, only an MR dP/dt cutoff of < 570 mmHg was predictive of adverse outcome [HR 1.63 95% CI 1.01–2.62 (p = 0.047)].A total of 7/8 parameters of RV systolic function were predictive of 2-year outcome, with study cutoffs like international guidelines. A cutoff of < −1.8 sWith cutoffs broadly like the ESC guidelines, we identified RV dysfunction to be associated with adverse prognosis, whereas LVEF could not identify patients at risk. Acute heart failure (AHF) is a leading cause of hospitalization , 2 and cLeft ventricular ejection fraction (LVEF) is routinely used as a surrogate for global left ventricular (LV) performance, but the evaluation of LV function remains challenging. Strain imaging has confirmed that a preserved EF does not guarantee “normal” systolic function , 8 and tchronic HF  dysfunction has trailed the LV , 22 despWe hypothesized that RV, rather than LV, systolic dysfunction may be more closely associated with long-term outcomes in AHF. To investigate this, we retrospectively used the study cohort of a prospective, observational study—the Mitral Regurgitation in Acute Heart Failure (MRAHF) study—to evaluate a battery of guideline-suggested and innovative assessments of systolic function of both RV and the LV.The MRAHF study methods are previously published . In summParticipants were followed up for 24 months and assessed by all-cause mortality through the United Kingdom summary care record system and by the online software Evolve™  for patient records, including death certificates, used at our hospital.Trial oversight was by the Ashford and St Peter’s NHS Trust Research and Development team and was approved by the institutional review board and ethics committee. All patients gave written informed consent before enrollment in the study. All authors had access to data and this manuscript for review. The experimental design and decision for publication were by Dr. A. Baltabaeva.Echocardiography was carried out with G.E. Vivid S70  and analyzed and stored using EchoPac v202.5 . Exams were performed with a dedicated protocol . Off-linThe assessment of the left and right atrial and ventricular geometry, RV and LV systolic, and data on calculation of systolic pulmonary artery pressures were obtained using a standard TTE minimum dataset approach advocated by the BSE .RV systolic function assessment parameters included were the tricuspid annular plane systolic excursion (TAPSE); RV Fractional Area Change (RV FAC); RV Tissue Doppler Imaging (TDI) peak systolic wave velocity (RV S’); two-dimensional RV ellipsoid ejection fraction (RVEF) ; RV GlobThe RV GLS was assessed by taking the mean of the peak systolic and end-systolic strain from the basal, mid, and apical RV free wall by off-line analysis on the EchoPac workstation (v202.5) using LV dedicated strain analysis. RV systole was defined as the period between pulmonary valve opening and closure. Deformation of the interventricular septum was not included. RV GLSR was obtained by averaging values from the peak strain rate before pulmonary valve closure and from the basal, mid, and apical free wall segments.LV systolic function assessment parameters included the LVEF; LV mitral regurgitation ΔP/Δt (LV MR dP/dt) when available; LV TDI lateral mitral annular peak systolic wave velocity (LV S’); LV Global Longitudinal Strain (LV GLS), and strain rate (LV GLSR).® Software Ltd., Belgium). Receiver Operator Curve (ROC) analyses were carried out on the previously discussed RV and LV systolic function parameters. The optimum cutoff for the prediction of 24-month mortality was estimated by identifying the sensitivity and specificity associated with the maximum Youden Index.Statistical analysis was carried out using MedCalc v.20.015  with available 2-year mortality data. Patients lost to follow-up were omitted from KM analysis.Patients with poor acoustic windows and unmeasurable parameters were also omitted from the analysis. The numbers available for each RV parameter are as follows: TAPSE 411/414, RVFAC 409/414, SPAP 401/414, TAPSE/SPAP 398/414, 2D RVEF 412/414, RV end-systole GLS 346/414, RV peak GLS 346/414, RV average GLSR 346/414 and RV S’ 398/414. For the LV: LVEF 411/414, LV S’ 404/414, LV MR dP/dT 352/414, LV GLS 411/414 and LV GLSR 411/414.If the unadjusted Cox regression model Log-rank tests from the ROC analysis failed to meet the 2-sided α-value of 0.05, further Cox regression models were constructed using ESC-guideline-specified thresholds, if not previously carried out . Once again, statistical significance was assessed using the Log-rank test.To determine whether the impact of LV and RV systolic assessment changes, and is independently associated with outcome, when analyzed as continuous variables instead of categorical variables with cutoffs, we constructed logistic regression models including 8 relevant cardiovascular demographic and clinical comorbidities previously included in the original results of the MRAHF study . These wThese models included 2 continuous, global assessments of LV and RV systolic function, LVEF and RV FAC, or LVEF and RVEF. We included both a guideline-directed assessment (RVEF) and a more experimental assessment (2D RVEF) to cross-reference the importance of RV global systolic performance with any method of assessment. In these models, the dependent variable was the binary outcome of survival vs. mortality at 2 years. The Enter method was used where all variables were included in a single step. The significance level was defined at a threshold of 0.05 and the odds ratio was calculated with 95% confidence intervals.p = 0.005)]. The cutoff of 35% for RV FAC was also associated with a worse 2-year prognosis for impaired vs. preserved FAC [HR 1.38 95% CI 1.00–1.89 (p = 0.049)]. Using an ESC-suggested 3-phenotype model of HF, LVEF was assessed in a 3-way comparison of > 50, 41–49, and < 50%, but these cutoffs were not significantly associated with outcome ]. The only RV parameter which was not significantly associated with a worse outcome was the RV S’ velocity ≤ 0.09 m/s vs. > 0.09 m/s (p = 0.170). The unadjusted Kaplan–Meier curves of these cutoffs are displayed in p = 0.169)  .p = 0.047)] ] . The unap = 0.028)] and LVEF was not (p = 0.794). Age, CKD, and COPD were also independent predictors of outcome. The model area under the ROC curve (AUC) was 0.744 (95% CI 0.699–0.786). To investigate if this effect was limited only to FAC, we also included another global assessment of RV systolic function with the ellipsoid assessment of RV ejection fraction, which was also an independent predictor of outcome OR 0.98 [95% CI 0.96–1.00 (p = 0.01)] ] .This study characterized the prognostic impact of a battery of RV and LV systolic non-invasive assessments by echocardiography. The study-specific cutoffs for 13 parameters of systolic RV and LV function were broadly like the ESC guidelines, except for LV GLS. Overall, this study suggests that poor RV function determines outcome in AHF.Most RV systolic assessments were associated with adverse outcome at a 2-year follow-up and this study confirmed the prognostic strength of standard parameters of RV function such as TAPSE and RVFAC which have well-established evidence in risk stratification for chronic heart failure patients –35. ThisRV longitudinal deformation obtained from the speckle-tracking technique has already been proven to be of prognostic importance despite load dependency  across a–1 may be of relevance to further research on the role of echo assessment of RV strain rate analysis.In this analysis, we used RV free wall strain rather than RV global strain to exclude the septum which is largely influenced by LV myocardial function . MeanwhiTo test the importance of RV function, we applied several other innovative assessments of RV systolic function which are not part of international guidelines. We applied a two-dimensional ellipsoid model to estimate RVEF which has previously been confirmed to be non-inferior to TAPSE and RV FAC in this cohort of patients . In our We also included the TAPSE/SPAP ratio, a relatively novel estimate of the right ventricular-vascular coupling to adjust to afterload caused by the left heart disease. It has been suggested to predict the outcome in heart failure with preserved ejection fraction (HFpEF)  and pulmGiven the good correlation of our study dataset to international guideline cutoffs, the cutoffs for more novel assessments such as 2D RVEF and TAPSE/SPAP ratios provided here may be of relevance for further research. Subject to confirmation by future studies in AHF, we think that 2D echo-derived RVEF and the SPAP/TAPSE ratio have the potential to play a significant role in clinical practice given both the ease of echo data acquisition and their potential prognostic significance.RV S’ was the only right-sided parameter that failed to reliably predict the outcome. This may be the result of angle-dependency which becomes an issue with RV remodeling and image acquisition in an acute setting where time limitations for scanning the unwell patient do not allow correct positioning of echo windows.Unlike RV function parameters, LVEF and most of the LV systolic function parameters were not associated with the outcome when used either as a binary cutoff, or in a guideline-directed 3-way comparisons of HFpEF, heart failure with mildly reduced ejection fraction (HFmrEF), and heart failure with reduced ejection fraction (HFrEF).The evaluation of ESC-suggested cutoffs for HFpEF, HFmrEF, and HFrEF echoed the results of retrospective analysis of the ASCEND-HF study  with a pIn the most recent guidelines of chamber quantification from EACVI/ESC, a value of −20% is identified to be suggestive of “healthy” myocardial strain  but no cThe only assessment of LV systolic function which displayed a discriminatory capacity for outcome was the MR dP/dt. This is a relatively load-independent reflection of global left ventricular contractility  which coThere are several limitations of this study. It was conducted at a single center which limits the generalizability of its findings and further confirmatory studies are warranted. We have not further investigated LVEF as a continuous variable in the sub-set of individuals with significantly impaired EF , where there is evidence for worsening outcome as LVEF deteriorates further . HoweverEcho assessment of RV strain was adapted from the LV strain analysis software with timing used from pulmonary valve opening and closure, ideally, an LV-specific software should be used. We have also not carried out a multivariate analysis of every RV parameter which was shown to be predictive of the outcome of an unadjusted assessment. However, we selected two global assessments of RV systolic function (RVFAC and RVEF) and performed logistic regression analysis with cofounders selected from our previous MRAHF study results. We selected RVFAC as a guideline-directed and RVEF as a more experimental parameter.In patients presenting with AHF, RV decompensation, confirmed by both load-dependent and independent parameters, is the main determinant of a long-term outcome. We have tested the novel parameters of RV function which proved to be feasible and significant as additional tools for standard RV assessment. This study suggests that a combination of left heart-induced afterload and depleted RV myocardial reserve plays an important role. This highlights the need to move past an overly simplistic reliance on the LV ejection fraction when assessing cardiac performance in AHF. More attention should be paid to LV dP/dt when the MR jet is available for accurate assessment.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Ashford and St. Peter’s NHS Trust Institutional Review Board and Ethics Committee. The patients/participants provided their written informed consent to participate in this study.AB developed the experimental design with inputs from IB, DF, IJ, and PS. MB and AB wrote the manuscript with editing available to all authors. MB carried out the statistical analysis. AB and MB made the final decision for submission. All authors had access to the manuscript and data before publication.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.


Fontan surgery by step-wise completing the isolation of originally mixed pulmonary and systemic circulation provides an operative approach for functional single-ventricle patients not amenable to biventricular repair and allows their survival into adulthood. In the absence of a subpulmonic pumping chamber, however, the unphysiological Fontan circulation consequently results in diminished cardiac output and elevated central venous pressure, in which multiple short-term or long-term complications may develop. Current understanding of the Fontan-associated complications, particularly toward etiology and pathophysiology, is extremely incomplete. What’s more, ongoing efforts have been made to manage these complications to weaken the Fontan-associated adverse impact and improve the life quality, but strategies are ill-defined. Herein, this review summarizes recent studies on cardiac and non-cardiac complications associated with Fontan circulation, focusing on significance or severity, etiology, pathophysiology, prevalence, risk factors, surveillance, or diagnosis. From the perspective of surgeons, we also discuss the management of the Fontan circulation based on current evidence, including post-operative administration of antithrombotic agents, ablation, pacemaker implantation, mechanical circulatory support, and final orthotopic heart transplantation, etc., to standardize diagnosis and treatment in the future. Functional single ventricle (FSV) is a heterogeneous spectrum of congenital heart disease (CHD), encompassing double inlet atrioventricular connection, absence of one atrioventricular connection, unbalanced common atrioventricular canal defect, single ventricular heterotaxia syndrome, and hypoplastic left heart syndrome (HLHS). As the most complex CHD, it is uniformly fatal without intervention.Fontan surgery that separates pulmonary and systemic circulation by the creation of venous-to-pulmonary connection for passive delivery of deoxygenated blood into the lungs and utilization of the sole FSV to maintain the systemic circulation, provides palliative strategies for FSV patients. It was first described by Fontan and Baudet in 1971 to innovatively repair tricuspid atresia . FurtherDespite enormous progress, the distinct Fontan circulation in the absence of a sub-pulmonic pumping chamber will lead to diminished cardiac output, elevated central venous pressure, and non-pulsatile pulmonary blood flow, thereby inevitably a cascade of short-term or long-term complications. Considerable efforts have been made to investigate the possible complications and explore possible therapeutic interventions, aiming to minimize the adverse effect, standardize the post-operative management, and improve the life quality of Fontan patients.Therefore, in this review, we discuss the latest research on cardiac and non-cardiac complications associated with Fontan circulation, involving significance or severity, etiology, pathophysiology, prevalence, risk factors, surveillance or diagnosis, and general treatment. What’s more, current management strategies including post-operative anticoagulation agent administration, ablation, pacing, mechanical circulatory support (MCS), and heart transplantation are also introduced from the surgeon’s point of view.Atrioventricular valve regurgitation (AVVR) is a frequent cardiac complication in Fontan circulation, which adversely impacts long-term outcomes in terms of increasing the risk of heart transplantation or death. Although the underlying pathophysiology remains incompletely clear, AVVR is considered to be attributed to a structural aberration of valve apparatus, as well as functional ventricular alteration. Structural abnormalities dominantly lead to AVVR and may take place at any part of the valve apparatus, such as abnormal commissures and clefts, shortened or elongated chordae, and dysplastic leaflets. As for functional etiologies, Fontan surgery exposes patients to a chronic volume overload resulting from aortic valve regurgitation or aortopulmonary collaterals, so that AVVR may evolve over time. Alteration in hemodynamics at different stages can also result in dysfunction of valve apparatus. It was verified that Fontan patients with common atrioventricular valves inherently suffered from sustained attrition of valve function .Imaging modalities that can accurately assess valve anatomy and function encompass transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), 3-dimensional echocardiography, computed tomography (CT), and cardiac magnetic resonance (CMR). Multiple modality imaging is recommended before next-step decision-making as each type of imaging modality has a unique advantage, as well as constraints. However, management strategies for AVVR have not been well-established. Drug treatment including diuretic therapy and afterload reduction can be attempted, but more evidence concerning the effect of these medications is required. Surgical intervention should be considered if AVVR seriously impacts patients’ life quality even after pharmacotherapy. AVVR historically used to be regarded as a contraindication for Fontan surgery. Over the years, concomitant repair or replacement of AVV during Fontan surgery has gradually been performed nowadays. The strategies of surgical intervention in terms of regurgitation severity stratification, as well as optimal timing for AVVR intervention, are not well-established. AVV repair is recommended in those with FSV and atrioventricular septal defects if AVVR exceeds a moderate degree in some centers.via a second atrioventricular node or an accessory pathway, atrioventricular nodal, focal atrial tachycardia, and reentrant circuits. There was also a distinctly deranged autonomic nervous control in the heart in terms of reduced baroreflex sensitivity and heart rate variability after Fontan completion. FSV individuals with prominent right atrial dilation presented distinct suppression of the sympathetic system in contrast to the parasympathetic system  and Brain Natriuretic Peptide (BNP) are clinically common biomarkers to identify cardiac dysfunction. It is also applicable to FSV physiology and further reflects the extent of hemodynamic overloading, as well as the long-term outcome. However, BNP and NT-proBNP levels have been elevated before Fontan completion. And there was no significant difference in the BNP levels between asymptomatic ventricular dysfunction FSV patients and healthy controls. Therefore, the BNP and NT-proBNP are more appropriate for detecting the progression of heart failure by sequential measurement in FSV physiology . ConventThe diuretics regimen to reduce the afterload is efficient to relieve symptoms in this setting. But there is debate over whether beta-blockers or renin-angiotensin-aldosterone inhibitors benefit the treatment of ventricular dysfunction in Fontan patients.Fontan-associated liver disease (FALD), an array of congestive hepatopathy consisting of liver fibrosis, cirrhosis, and even carcinoma, is a ubiquitous non-cardiac complication encountered in FSV patients under unique Fontan hemodynamics. The natural history has been well described, mainly encompassing three main stages, as summarized in Regular and comprehensive surveillance is crucial to identify the development of FALD. It is recommended that Fontan patients with HCC are supposed to undergo cancer screening every 6 months. Liver biopsy represents the gold standard in identifying and assessing hepato-fibrosis in FALD. However, the biopsy-associated bleeding complication on account of elevated systemic venous pressure and the frequent use of anticoagulation drugs may limit its universal surveillance in FALD. Non-invasive surveillance tools like serology and imaging modalities may be complementary. Liver enzymes are frequently normal until the late FALD, failing to early identify FALD and assess its severity. Model for end-stage liver disease (MELD), Pediatric End-stage Liver Disease (PELD), and aspartate-to-platelet ratio index (APRI) have been verified as useful serum markers as they are correlated with liver stiffness and fibrosis. However, these tools relied on serum INR derangements, thereby not applicable in those Fontan patients with warfarin therapy. Alternatively, the MELD XI score that excludes INR and uses serum creatinine and serum bilirubin may also monitor and assess FALD in such population. Imaging modalities are capable of non-invasively providing detailed, complementary, and accurate assessments of liver structure, morphology, and hemodynamics in Fontan patients. Although it is relatively insensitive in identifying the fibrotic alteration, abdominal ultrasonography (US) is an important evaluation imaging modality as a consequence of providing gross structural features and hemodynamic information. Heterogeneous surface nodularity or hepatic echotexture was a prevalent finding, which was correlated with time after the Fontan surgery . BesidesDespite histological findings and imaging results, decision-making is hard because of the failure to accurately assess residual liver function. The prevention and treatment of FALD are dependent on the Fontan circulation optimization by medical or surgical interventions to reduce CVP or increase cardiac output. Heart-only transplantation is adequate and suitable for those FALD patients with only mild portal hypertension, normal hepatic vessel anatomy, preserved liver synthetic function, liver volume more than 800 ml, but no HCC. If there is advanced liver cirrhosis evidence in terms of clinical manifestations, imaging results, or biopsy findings, and if there is certain decompensation evidence, combined heart-liver transplantation can be taken into consideration as an alternative .N-acetyl glucosaminidase could also be considered to be routinely detected as they could not only effectively identify Fontan-associated tubular injury but also predict adverse outcomes in terms of non-elective cardiovascular death or hospitalization  and chronic kidney disease (CKD). Cardiopulmonary bypass, use of nephrotoxic medications, Fontan unique hemodynamic in terms of low cardiac output and elevated venous pressure, and hypoxemia may play a dominant role in the development of renal dysfunction. Fontan-related renal dysfunction seemed to be tolerable in the early post-operative period as similar 10-year survival rates were observed between Fontan patients with and without Fontan renal dysfunction . Clinicalization . AlthougThromboembolic events (TE) are a significant cause of morbidity and mortality in FSV patients with Fontan circulation. Although the development and mechanism of TE are incompletely defined, three factors of Virchow’s triad are involved: endothelial dysfunction, abnormal hemodynamics, and hypercoagulability. Specifically, endothelial dysfunction refers to the loss of antithrombotic factors, including Protein C, S, and antithrombin, and vasodilators like nitric oxide, as well as the increased prothrombotic products and vasoconstrictors, eventually resulting in a pro-thrombotic condition. The hemodynamics also alters, manifesting as often turbulent and non-pulsatile flow, which may predispose Fontan patients to develop TE. The reduction of antithrombin III, fibrinogen, protein C, plasminogen, factor II, V, VII, IX, and X were detected in both the pre-Glenn and post-Fontan patients, suggesting the hypercoagulable state due to an imbalance between coagulation and anticoagulation system occurred prior to Fontan surgery and maintained throughout the entire post-Fontan period , 26. Livvia both an upper and lower extremity is recommended to improve imaging quality.Given the significant association with mortality, the early diagnosis of TE is of paramount. D-dimer detection might be useful in identifying intracardiac thrombus in Fontan circulation. The proper cutoff value to rule out thrombus within the cardiac chamber was 1.8 μg/mL, with 85% sensitivity and 92% specificity . ImagingThe pharmacotherapy medication to prevent and treat thromboembolic complications predominantly relies on the control of atrial arrhythmias, as well as thromboprophylaxis. It has been recommended with 2C Class by the American College of Chest Physician Evidence-Based Clinical Practice Guidelines for Antithrombotic Therapy and the Prevention of Thrombosis to routinely post-operative use of unfractionated heparin (UFH) in those neonates and children with either bilateral cavopulmonary shunt or bidirectional Glenn operation. Despite the recommendations, thromboprophylaxis strategies vary among centers, encompassing the single-use of aspirin, warfarin, UFH, and enoxaparin, or combined use of aspirin and low-molecular-weight heparin (LMWH), aspirin and warfarin, UFH and aspirin, and UFH and LMWH.Protein-losing enteropathy is an unusual but devastating complication with a remitting and relapse course, characterized by massive loss of protein into the digestive tract leading to low total protein and serum albumin levels, hypercoagulability, and immunodeficiency on account of enteric loss of lymphocytes and immunoglobulins. Patients may manifest abdominal cramps, chronic diarrhea, malnutrition, peripheral edema, persistent pleural effusions, ascites, and decreased bone mineral density. The underlying pathophysiology and etiology appear to be multiple. First, elevated systemic venous pressure resulting from pulmonary artery branch stenosis, Fontan pathway obstruction, and elevated atrial pressures associated with arrhythmias, AV-valve regurgitation, and ventricular diastolic dysfunction would predispose Fontan patients to generate PLE . SecondlElevation of α-1 antitrypsin clearance in 24-h collected stool samples remains the gold standard test in PLE diagnosis. Because of the difficulty in collecting sufficient stool samples, it is also agreed with alternative criteria in terms of clinical edema, hypoalbuminemia together with an elevated α-1 antitrypsin based on a single stool specimen after excluding other causes. Technetium-99 m labeled human serum albumin scintigraphy has also been adopted to image and diagnose the PLE since its first attempt in 1986 . It provvia a combination of low sodium, high medium-chain triglycerides, low fat less than 25% calories, and high protein over 2 g/kg/d  is a sparse but potentially fatal disorder in Fontan patients, characterized by the generation and expectoration of cohesive and obstructive bronchial casts. But PB can occur more acutely and perilously in contrast to PLE. The cast is composed of dominating mucinous components but rare chylous and inflammatory components, with sizes ranging from a small segmental bronchus to the whole bronchial tree. In this context, patients may have wheezing, shortness of breath, coughing, chest pain, and even fatal asphyxia. Although the pathogenesis of PB in Fontan patients remains poorly understood, it may share some mechanisms with PLE. Inherent hemodynamic changes in Fontan patients in terms of elevated systemic venous pressure, diminished cardiac output, and elevated pulmonary artery pressure are responsible for the injury of the alveolar-capillary barrier and mucosal integrity, which consequently leads to cast formation There would be possible opacification of the involved lung field owing to full or partial atelectasis on chest X-ray examination, which is not sensitive and specific enough. The current diagnosis of PB is based on the evident bronchial casts by expectoration or bronchoscopy removal. Lymphangiography capable of discovering aberrant lymphatic vessels, such as thoracic duct dilation, lymphatic collateral formation, and lymphangiectasia, can be a complementary tool in confirming the PB diagnosis. In general, the strategy of PB management differs from the clinical status. The acute attack of PB should maintain the airway unimpeded immediately by promoting cast expectoration, as well as invasive removal of the cast. While the primary focus of chronic PB is to maintain respiratory tract clear and identify the underlying reason for a cast. The pharmacological therapy for PB now is highly anecdotal, covering the bronchodilators, antibiotics, corticosteroids, mucolytics, aerosolized heparin, tissue plasminogen activator, and urokinase in a myriad of integration. Given the role of lymphatic circulation in the development of PB, percutaneous embolization of abnormal lymphatic fistulae that enabled the prevention of lymphatic leakage showed satisfying outcomes and thereby might become a promising interventional treatment . The comCardiac and non-cardiac complications related to Fontan surgery are summarized in The management of Fontan-associated thrombosis typically includes anticoagulant therapy, thrombolytic treatment, and embolectomy. The decision-making is heavily determined by the potential pathogenic factor and the size and location of the thrombus. Vitamin K antagonists are recommended with Class I in those with prior atrial arrhythmias, TE, and suspected or diagnosed thrombus according to the 2018 ACHD guidelines. As for those with asymptomatic thrombus, antithrombotic treatment is recommended with Class IIb .As for those without TE yet, thromboprophylaxis may be paramount and appropriate in Fontan management, given the significant association of TE with morbidity and mortality. Indeed, prophylactic administration of antithrombotic drugs has increasingly become routine in Fontan patients as it was associated with a lower risk of hospitalization and death, and a lower TE rate . AspirinBased on current evidence, several guidelines have been proposed to guide the decision-making in the thromboprophylaxis management of Fontan patients. UFH or ASA combined with an additional vitamin K antagonist are recommended for those Fontan children in the Guidelines from the American College of Chest Physicians in 2012 . A Scienvia a fenestration, trans-baffle, or trans-conduit puncture into the atrium. When sufficient cavo-atrial overlap presents in ECC Fontan, a trans-caval puncture through a hepatic vein or inferior vena cava adjacent to the pulmonary venous atrium wall appeared to be feasible  is a well-established modality with short-term support for the isolated or combined failure of the heart or lungs. Common indications of initiation of ECMO in post-operative CHD patients comprise extracorporeal cardiopulmonary resuscitation, hemodynamically unstable arrhythmias, refractory low cardiac output, thrombogenesis within the systemic-to-pulmonary shunts in FSV patients, persistent hypoxemia, and weaning failure from the cardiopulmonary bypass. ECMO support in FSV patients with Glenn or Fontan physiology is challenging owing to additional complexity in surgical anatomy and physiology. Technically, sufficient venous drainage through multi-site cannulation and venous decompression followed by appropriate ECMO management are imperative components in achieving successful ECMO. Veno-arterial ECMO (VA ECMO) is the common supportive modality, with a mortality rate of 57% . The pooIn contrast, venovenous ECMO (VV ECMO) is another supportive modality for FSV patients with pure ventilation or oxygenation impairment. Aydin et al. described the outcome of FSV patients with the respiratory disease under VV ECMO support, using the data from the Extracorporeal Life Support Organization Registry. It showed a survival rate of 48%, comparable to those FSV patients with cardiac failure undergoing VA ECMO . The renThe application of ventricle-assist devices (VAD) as a bridge to transplantation, recovery, or destination therapy has facilitated the management of advanced ventricular failure by minimizing adverse events, decreasing mortality, and improving life quality. In Fontan patients, it is also capable of improving the hemodynamics by unloading the FSV and augmenting the cardiac output. A recent retrospective report from the Advanced Cardiac Therapies Improving Outcomes Network registry showed that over 2/3 of recipients implanted with VAD could be successfully supported to undergo consequent heart transplantation . TechnicThe type of implanted device is supposed to be fully considered because anatomy, size, and symptoms may vary and therefore complicate the device selection. Although it is in infancy, increasing case reports and series have demonstrated the successful support of several current available VADs in Fontan patients with ventricular failure, including the Berlin Heart EXCOR, HeartWare, and HeartMate 3. Current experience regarding the VAD support in Fontan patients is limited, and further investigation to decide the type of device, patient selection, and optimal timing is necessary.Heart transplantation represents an ultimate therapeutic approach to replace the originated heart in Fontan failure. Fontan patients are the most common and rapidly growing population in CHD referred for heart transplantation owing to inherent vulnerabilities, with a prevalence of 0.7–6.8% . Early iAs mentioned above, the unique and unphysiological Fontan hemodynamics is the main trigger of a series of Fontan-associated complications. The characterization of abnormal hemodynamic or blood flow patterns is therefore vital. Computational flow dynamics (CFD) and 4-dimensional flow magnetic resonance imaging (4D flow MRI) have emerged as unprecedented imaging modalities, allowing the visualization and quantification of blood flow characteristics. 4D flow MRI refers to the acquisition of 3-dimensional time-resolved volume with velocity-encoding in all three directions throughout the cardiac cycle, while CFD involves the creation of a 3-dimensional model by numerical analysis based on 3-dimensional rotational angiography, CT, or MRI. Both CFD and 4D flow MRI have been increasingly applied in Fontan patients and shown abnormal blood flow patterns distinct from other populations, providing novel insights into the hemodynamic response and mechanism of Fontan failure. Reduced direct flow and augmented residual volume were principal hemodynamic features in Fontan patients with hypoplastic right heart syndrome and HLHS . There wApart from the elucidation of hemodynamic alteration in Fontan circulation, CFD and 4D flow MRI, capable of patient-specific computational modeling, can also aid in customized surgical planning for Fontan patients. The current optimization of patient-specific TCPC design focus on two major aspects: (1) minimization of the energy loss and (2) balance of hepatic blood distribution. In this regard, Trusty et al. modified the TCPC with bifurcated Y-grafts that directed the hepatic blood flow into both the right pulmonary artery and left pulmonary artery and explored computational fluid dynamics for the evaluation of energy loss and hepatic flow distribution. The results showed that a more balanced hepatic flow distribution was obtained without increasing TCPC resistance, highlighting the Y-graft modification value in Fontan completion .Therefore, the application of CFD and 4D flow MRI will not only improve the understanding of hemodynamic mechanisms that predict the complications early but also benefit the design of patient-specific surgery plans. Ongoing methodological improvements would increase the reliability of hemodynamic characterization, the accuracy of the customized computational models, and the feasibility of the next-step surgical plan.Fontan ventricular assist device has emerged as an area of growing interest on account of its potential to decongest venous pressure, overcome the elevated pulmonary resistance, augment the cardiac output, and thereby address the Fontan circulatory insufficiency. It was initially described by de Leval to deal with the Fontan paradox in terms of coexisting reduced cardiac output and elevated central venous pressure in contrast to the conventional MCS support . Since tThe EC Fontan involves the introduction of man-made grafts, homografts, or xenografts, which is disadvantageous due to the inability to grow, as well as susceptibility to develop TE, stenosis, chronic infection, and calcification. Tissue-engineered vascular grafts (TEVG) through the integration of synthetic or natural degradable scaffold and seeded cells hold considerable promise to address these obstacles. After implantation, the TEVG goes through the degradation and remodeling resulting from the induced host cell infiltration over time, ultimately replaced by the autologously regenerative vascular tissue. The neotissue formation was mediated by an early inflammation-driven response followed by a mechano-induced response . These gin vitro and in vivo, mainly targeting the enhancement of angiogenesis and minimization of oxidative stress. Strikingly, some clinical trials have been sponsored and completed to boost the clinical translation of stem cell therapy in HLHS treatment (Stem cell therapy holds promising potential, which has been employed to discover the underlying mechanism of malformation development, as well as preserve or improve ventricular performance in FSV patients, most commonly in HLHS. It is the most complex and common type of FSV abnormalities, characterized by underdevelopment of the mitral valve, LV, outflow structures, and aorta. Despite advancements in medical management and surgery evolution that increase the likelihood of surviving into adulthood, the RV in the HLHS physiology inherently presents vulnerability and intolerance to chronic pressure overloading, therefore predisposed to early ventricular failure. There was a reduced angiogenic response of RV in the HLHS patients in the context of pressure overloading, thereby impeding the delivery of nutrients and oxygen to cardiomyocytes and further leading to myocardial dysfunction . The devreatment .Although tremendous technical obstacles, as well as safety and efficacy, remain in the current era, stem cell therapies and cardiac regenerative medicine are believed to benefit the future management and treatment of HLHS. The clinical translation of stem cell therapy in HLHS treatment can be expected if issues such as the timing of intervention, method, dosing of administration, and optimal stem cell type are defined in the future.HY was responsible for the conception and design of the present work. JM performed the literature search and drafted the manuscript. All authors took part in manuscript revision and approved the final version of the manuscript.


Sympathetic nervous system activation in patients with heart failure is one of the main pathophysiologic mechanisms associated with the worse outcomes. Pharmacotherapies targeting neurohormonal activation have been at the center of heart failure management. Despite the advancement of therapies and the available treatments, heart failure continues to have an overall poor prognosis. Renal denervation was originally developed to lower systemic blood pressure in patients with poorly controlled hypertension, by modulating sympathetic outflow. However, more recently, multiple studies have investigated the effect of renal denervation in heart failure patients with both preserved (HFpEF) and reduced ejection fractions (HFrEF). This paper provides an overview of the potential effect of renal denervation in altering the various pathophysiologic, sympathetically mediated pathways that contribute to heart failure, and reviews the literature that supports its future use in those patients. Heart failure remains among the leading causes of morbidity and mortality in the United States, with a continuously increasing prevalence of the disease . DespiteIn chronic heart failure, the complex interplay between the neuro-hormonal, sympathetic, and inflammatory pathways provides the pathophysiologic milieu for cardiac remodeling . RAAS acThere is a significant interplay between the renal sympathetic activity and the central nervous system creating a continuous feedback loop between the two organs  11]. Re. Re11]. Hormonal and sympathetic activation contribute to myocardial remodeling, which can initially be adaptive in maintaining cardiac output and tissue perfusion. This remodeling involves myocardial hypertrophy and collagen synthesis under the effect of transcriptional protein activation . An exceNE spillover in the kidneys is associated with a worse prognosis . Since tRecently, there has been an increasing interest in RDN as a treatment for chronic heart failure and tachy-arrhythmias, such as atrial fibrillation, with multiple studies demonstrating its efficacy, up to 1-year follow-up ,22. As pThe ACC/AHA define heart failure with reduced ejection fraction (HFrEF) as systolic dysfunction with left ventricular ejection fraction (LVEF) <40%, with or without symptoms of congestion . As prevIt is important to note that, while most of the prior studies demonstrated a favorable RDN effect via the downregulation of SNS, hence the modulation of renal NE, adrenoceptor expression, and RAAS pathway, a novel finding was the effect of RDN on neprilysin levels. Neprilysin is a metallopeptidase responsible for the degradation of several peptides, including ANP, BNP, bradykinin, and Angiotensin 2. Recently neprilysin inhibition, with a concomitant increase in the circulating plasma natriuretic peptides, has become of great interest in the management of HFrEF. Large scale clinical trials, such as PARADIGM-HF, demonstrated that combining a neprilysin inhibitor (Sacubitril) with valsartan was superior to the standard guideline-directed therapy with a RAAS inhibitor alone  . PolhemuApart from the animal models of heart failure, there has been limited clinical data with RDN as a therapy for heart failure . Davis eHeart failure with preserved ejection fraction (HFpEF) is a systemic disorder characterized by normal left ventricular ejection fraction, elevated filling pressures, and increased ventricular and arterial stiffness . It is hp = 0.033) [p  = 0 .006) [The patients with chronic heart failure are predisposed to various types of atrial or ventricular tachyarrhythmias, including atrial fibrillation (afib) and ventricular tachycardia. In the patients who suffer myocardial infarction or develop heart failure, autonomic dysregulation leads to an excessive sympathetic drive, and compensatory mechanisms, as previously discussed, become a nidus for cardiac pathology . This sy= 0.033) . ERADICA 0 .006) . More th 0 .006) . More re 0 .006) . The afoHeart failure, regardless of LV function, continues to carry a poor prognosis and is associated with a significant burden on health care systems. Pharmacotherapy targeting various neuro-hormonal pathways was shown to improve clinical outcomes in patients with reduced ejection fraction, yet not so much in preserved LV function. Recently, SGLT2 antagonists have emerged on the front line of pharmacotherapy for heart failure and have shown for the first time an improvement in clinical outcomes in patients with preserved ejection fraction ,58,59. HChronic heart failure continues to impose a major challenge for clinicians, due to its heterogeneity and the complexity of the syndrome, with incompletely understood pathophysiological mechanisms. The resultant economic burden of the syndrome continues to rise worldwide, as does the prevalence of the disease. The kidneys play a vital role in SNS activation and modulation and are a critical part of the feedback loop between the heart, the brain, and the vasculature. Targeting renal afferent and efferent sympathetic nerves via alternative therapeutic strategies, such as RDN, has proven to be safe, feasible, and efficacious. Through its simultaneous action on various neuro-hormonal pathways, including renal NE spillover, RAAS and neprilysin pathways, RDN has shown to improve ejection fraction, improve diastolic parameters, and regress hypertrophic and maladaptive pathogenic remodeling of the cardiac tissue in animal models and small clinical studies. Additionally, its anti-arrhythmic potential may prove vital in improving heart failure outcomes. RDN offers a therapeutic promise in heart failure patients. We look forward to the results of several larger, randomized controlled trials that are underway to provide further clarity and evidence of the role of RDN in the management of heart failure.


Heart failure in children differs substantially from the adult population. Clinical characteristics of pediatric diastolic heart failure has rarely been reported. In this study, we aimed to summary the causes, clinical features, lab tests, and treatment effect of pediatric diastolic heart failure.This study was a single center, retrospective study conducted in Children’s Hospital of Chongqing Medical University. Children who were diagnosed with diastolic heart failure (DHF) without systolic heart failure (SHF) between 2006 and 2014 were included. Meanwhile, SHF (without DHF) cases were also collected from 2013 to 2014.A total of 421 DHF and 42 SHF cases were included. The average age of pediatric DHF was 1.89 ± 3.29 years old, significant younger than that of SHF (4.65 ± 4.90). The top three cardiovascular causes of DHF were complex congenital heart malformations (53.4%), simple congenital heart defect (15.7%), and cardiomyopathy (7.4%). Alternatively, number of cardiomyopathy cases (57.1%) ranked first in SHF group. Simple congenital heart diseases (CHDs) rarely caused SHF. The most common symptom and sign were tachypnea and hepatomegaly in pediatric HF. Symptoms like cyanosis, feeding difficulty, be fidgety, pale, fatigue, and edema were valuable in differential diagnosis of DHF and SHF in children. B-type natriuretic peptide (BNP) increase was found in 36.9% of DHF children, and 60% in SHF patients. Sensitivity of BNP greater than 100 pg/ml in diagnosis of DHF was 0.37, and specificity of it was 0.86. Diastolic function indicators, such as E/A (early wave/late wave) ratio, IVRT (isovolumic relaxation time) were significant recovered after treatment in DHF patients. Less therapeutic benefits were achieved in children with cardiomyopathy induced DHF, in compared with non-cardiomyopathy patients.Pediatric DHF and SHF were largely different in primary causes, clinical symptoms and signs and short-term prognosis. There was a limit diagnostic value of BNP with 100 pg/ml as cut-off value in pediatric DHF. Larger, multicenter studies of pediatric DHF are required in the future. Heart failure in children is a serious public health concern, as the costs are considerably higher for children than adults because of the frequent need for surgical or catheter-based intervention . The demDiastolic heart failure has been referred to as heart failure with preserved ejection fraction (HFpEF) in recent years, and is characterized by signs and symptoms of heart failure and a left ventricular ejection fraction (LVEF) greater than 50% . DiastolThis was a retrospective study conducted in Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders. This study was approved by the Institutional Review Board of Children’s Hospital of Chongqing Medical University, Chongqing, China.A total of 421 DHF cases from October, 2006 to December, 2014 were collected. Meanwhile, 42 SHF cases from January, 2013 to December, 2014 were included. All those clinical data: general information, basic diseases, symptoms, signs, echocardiography reports, BNP levels, and treatments were summarized. Plasma BNP levels of 979 patients  form January, 2013 to December, 2014 were collected. BNP detection in our center was started in 2010, so number of DHF patient with BNP result was 130.Inclusion criteria:Diastolic heart failure: (1) to have heart failure symptoms and signs, Modified Ross Score  greater Systolic heart failure: (1) to have heart failure symptoms and signs, Modified Ross Score greater than or equal to 3 points; (2) LVEF less than 50%.2, Fisher’s Exact test and t-test, respectively. Measurement data expressed as mean ± standard deviation (x ± s). Statistical analysis was performed using SPSS . p-Value less than 0.05 was considered statistically significant.The categorical data and continuous data were analyzed by χp < 0.001.As shown in Primary diseases of pediatric DHF and SHF were illustrated in p < 0.01. On the contrary, pale complexion (15.9 vs. 35.7%), fatigue (12.3 vs. 33.3%), and edema (8.1 vs. 23.8%) were more common symptoms in SHF, when compared to DHF patients, p < 0.01. Early diagnosis and effective treatment of HF remain significant challenges. Also, diastolic HF is an important but as yet poorly elucidated topic in the pediatric literature. Data from our study indicated that in children with heart diseases, pediatricians should be alert of DHF when symptoms such as tachypnea, cyanosis and poor appetite, and sign like hepatomegaly are found in their patients.As shown in In adult HF, the most common biomarker is BNP and/or its precursor protein N-terminal prohormone of BNP (NT-proBNP) . BNP is The treatment of heart failure in children depends on the underlying cause and the child’s age . TherefoApproximately half the adult patients with newly diagnosed heart failure have “diastolic heart failure” with preserved systolic function . The preWe found the average age of DHF children was younger than that of SHF patients. This could be explained by the age differences among those primary cardiovascular diseases. As the use of three- or four-dimension ultrasound in prenatal examination and improved screening for CHDs postnatally, CHDs are now more frequently to be found at an earlier age. Alternatively, early diagnosis of CMs is always difficult to accomplish . NotablyOur data showed that tachypnea and hepatomegaly were the most common symptom and sign in pediatric heart failure, which are considered as the most reliable indicators in diagnosis and degree assessment (The ROSS Score)  of pediaB-type natriuretic peptide has been considered a primary and one of the most valuable markers in adult heart failure in many aspects, like diagnosis, degree assessment, prognosis, and treatment efficiency evaluation , 23. ButAt present, prognosis of DHF in adults is poor and irreversible, but in pediatric patients, treatment effect of DHF seems more promising, mainly because of two reasons: (1) most causes of pediatric DHF were congenital heart defects, which is more curable in compared with cardiomyopathy and ischemic heart diseases; (2) most children with DHF were at younger age, those unmatured hearts and their functions were more recoverable.Pediatric heart failure is still largely unknown. A major future direction to improve treatment of heart failure in children is to obtain sufficient data from well-designed trials with adequate power to support treatment recommendations.There are some limitations of the present study. (1) A small sample size of SHF case, which means we cannot exclude the influence of few CHD case numbers in SHF group on constituent ratio of primary diseases of SHF. (2) The importance of genetic tests in CM patients has been increasingly recognized in recent years. Another limitation of this present study is that none of our CM patients completed genetic testing. The main reason was that most of the parents could not afford the genetic test, the test fee was quite expensive a decades ago. Fortunately, with the development of the economy and the cut of test price, more and more CM children underwent genetic test in our center, also in whole China. In future studies, we hope to report role of genetic factors in pediatric CMs and DHF. (3) Meanwhile, it is a pity that we failed to follow-up all our patients 3 months after discharge, in those 101 patients reexamined cardiac echo, none of them died in the first 3 months. That means we fail to compare the treatment between those patients who died and those who did not. We are expecting to compare that part in our prospective study in the near future.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Institutional Review Board of Children’s Hospital of Chongqing Medical University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.WX, TL, and JT contributed to the conception and design of this study. BP and WX organized the data and performed the statistical analysis. BP and DH drafted the manuscript. BP, DH, and HS wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This study aimed to explore the correlation between left ventricular (LV) myocardial work (MW) indices and invasively-derived LV stroke work index (SWI) in a cohort of patients with advanced heart failure (AHF) considered for heart transplantation.Left ventricular MW has emerged as a promising tool for diagnostic and prognostic purposes in heart failure (HF) but its relationship with hemodynamic data derived from right heart catheterization (RHC) has not been assessed in patients with advanced heart failure yet.Consecutive patients with AHF considered for heart transplantation from 2016 to 2021 performing RHC and echocardiography as part of the workup were included. Conventional LV functional parameters and LV MW indices, including LV global work index (GWI), LV global constructive work (GCW), LV global wasted work (GWW), LV global work efficiency (GWE), and other were calculated and compared with invasively-measured LV SWI.p = 0.031), whereas, LV ejection fraction (EF) did not . With regard to LV MW indices, some of them demonstrated correlation with LV SWI, particularly LV GWI , LV GCW , LV global positive work  and LV global systolic constructive work .The population included 44 patients. Median time between RHC and echocardiography was 0 days (IQR: 0–24). Median age was 60 years (IQR: 54–63). For the most part, etiology of HF was non-ischemic (61.4%) and all patients were either on class NYHA II (61.4%) or III (27.3%). Median left ventricular ejection fraction was 25% (IQR: 22.3–32.3), median NT-proBNP 1,377 pg/ml (IQR: 646–2570). LV global longitudinal strain (GLS) significantly correlated with LV SWI (r = –0.337; Among LV MW indices, LV GCW correlated better with invasively-derived SWI, potentially representing a powerful tool for a more comprehensive evaluation of myocardial function. The prevalence of people being affected by heart failure (HF) worldwide is incessantly increasing and is now over 60 millions . ConsensRight heart catheterization is a tremendously informative exam whose results far exceed a mere pressures measurement. Indeed, RHC provides data regarding flow and resistances, which give additional details about cardiopulmonary physiology. Moreover, measures of stroke work, representative of the area inscribed in the pressure-volume (PV) loop whether of the right or the left ventricle, can be easily derived from other data, bringing deeper insight into myocardial functioning, thus helping the clinician to better characterize the failing heart.The PV diagram is a well-known tool describing cardiac mechanics and energetics. However fascinating on a theoretical level, its applicability has long remained confined to research setting. A novel echocardiographic method derived from speckle tracking echocardiography (STE) analysis, called “Myocardial Work” (MW), has recently been introduced as a non-invasive derivative of PV curve . MW analMyocardial work has already emerged as a promising tool for various pathological conditions –16, bothAll consecutive patients with advanced heart failure (AHF) considered for HTX from 2016 to 2021 were retrospectively reviewed. Inclusion criteria were: RHC and echocardiography availability, informed consent from the patient. Exclusion criteria were: time between echocardiographic exam and RHC > 3 months, previous left ventricular assist device (LVAD) implantation, previous heart valve surgery/interventions, single chamber ventricular pacing and poor echocardiographic windows. The study was performed in accordance with the Declaration of Helsinki. Local ethical committee approved the study protocol.Patients’ baseline characteristics, vital signs, laboratory tests, medications, echocardiographic data and RHC parameters were retrospectively collected.All echocardiographic examinations were performed by experienced operators using GE Vivid E80/E95 equipped with an adult 1.5–4.3 MHz phased array transducer, and with an ECG continuously traced, according to the American Society of Echocardiography/European Association of Cardiovascular Imaging recommendations , 18.For STE analysis, endocardial borders and myocardium of all segments from the apical views  had to be clearly visualized throughout the whole cardiac circle and ECG track had to be present in each echocardiographic exam. Left ventricular speckle tracking strain is semi-automatically performed by the software in the three apical views and adjusted by the operator, in terms of region of interest (ROI) width and positioning, to optimize endomyocardial tracking. The software warns the operator whether a specific wall segment is not automatically recognized and they may manually adapt ROI and force analysis.For subsequent MW analysis, markers for aortic, and mitral valves opening and closure are required to set the beginning and the end of each main phase of cardiac cycle  and they were visually set from the apical long axis view. Moreover, brachial cuff blood pressure are needed to warp in time and amplitude the reference curve for left ventricular pressures estimation and the one detected at the time of echocardiography was used in order to conclude the analysis.Finally, the software’s output is a series of indices which depict the PS loop from various perspectives , 20. In Vascular access for RHC examination was obtained with ultrasound guidance through the internal jugular vein under local anesthesia. Adequate zero level was searched using the medium-thoracic line of the supine patient as a reference. Pulmonary artery catheters, also known as Swan-Ganz catheters, were used to measure central venous pressure (CVP), diastolic, and systolic right ventricular pressures, diastolic, systolic, and mean pulmonary artery pressures (PAP) and pulmonary capillary wedge pressure (PCWP). The height of PAP waves was manually measured. Cardiac output was derived by the thermodilution technique (average of five cardiac cycles with < 10% variation) and by the Fick equation. Cardiac index, stroke volume, and stroke volume index were derived indexing cardiac output for body surface area and dividing cardiac output and cardiac index for heart frequency, respectively. Vascular resistances were calculated by the following equations: [(mean pulmonary artery pressure–pulmonary capillary wedge pressure) × 80/cardiac output] for pulmonary vascular resistance and [ × 80/cardiac output] for systemic vascular resistance. LV stroke work index (SWI) was retrospectively calculated through the following formula:  × stroke volume index × 0.0136. All the other parameters were already calculated at the time of catheterization.p-value < 0,05 was considered statistically significant. Analysis was performed using SPSS, version 26 .Continuous data are presented as mean and standard deviation or as median and interquartile range, as appropriate. Kolmogorov–Smirnov test was used to verify normal distribution of variables. Categorical data are summarized as absolute and relative frequencies. Correlation was calculated using Pearson’s and Spearman’s correlation coefficients, as appropriate. Receiver operating characteristic curves were generated to assess predictive performance of STE-derivate indices for LV SWI. A n = 182). Among them, 86 patients were excluded because they had not performed RHC yet, whereas, five were excluded because of unavailable echo. Moreover, 46 patients were excluded according to exclusion criteria  and most of the patients were men (77.3%). Etiology of HF was predominantly non-ischemic (61.4%) and all patients were either on NYHA class II (61.4%) or III (27.3%). HF therapy is described in Median left ventricular end-diastolic diameter was 75 mm (IQR: 63–79) and median left ventricular ejection fraction (EF) was 25% IQR: 22–32). Mean right ventricular mid end-diastolic diameter was 31 ± 4 mm and mean fractional area chance was 39 ± 7%. Diastolic function was impaired, with a median E/e’ of 12 (IQR: 9–16). Median systolic pulmonary artery pressure was 27 mmHg (IQR: 25–44). Only 9.1% of patients had no or mild mitral regurgitation, whereas, only 4.6% of patients had at least moderate aortic regurgitation. Regarding STE parameters, global longitudinal strain (GLS) was impaired, with a median of –5% (IQR: –8—3) [normal range < –19.7% ], as wel–32. Mean2. RHC parameters are shown in Mean right atrial pressure was 7 ± 4 mmHg. Mean pulmonary artery pressure (mPAP) was increased (25 ± 10 mmHg) and median pulmonary capillary wedge pressure (PCWP) was 14 mmHg (IQR: 10–22). Mean vascular pulmonary resistance was 2.46 ± 1.19 mmHg/l/min. Mean LV SWI was 29.84 ± 9.51 mmHg*ml/mp = 0.050), whereas, GLS did . Among MW indices, GWI, GCW, GPW and GSCW significantly correlated with SWI . For the complete correlation analysis results, see p = 0.002).Among traditional parameters of LV systolic function, EF did not significantly correlate with SWI , followed by LV GCSW (AUC 0.818), LV GPW (AUC 0.800), LV GWI (AUC 0.735), and LV GLS (0.714). For ROC curves see , followeThe main findings of the study can be summarized as follows:1.Non-invasive measurement of stroke work through myocardial work (MW) calculation significantly correlated with invasively-derived stroke work index in a population of advanced heart failure patients.2.Among echocardiographic parameters of LV systolic function, correlation with invasive measures increases from classical indices to most recent ones.3.Ejection fraction is the less reliable tool to evaluate LV systolic function in patients with severely compromised EF, compared to advanced echocardiographic parameters.The measurement of work performed by the heart has long remained of difficult clinical applicability due to the invasiveness of catheterization. “Myocardial work,” a novel non-invasive echocardiographic method for calculation of work, has already proven its diagnostic and prognostic usefulness in various pathological conditions , 12, 13.Our results have shown a significant correlation between some indices of myocardial work and invasively-derived stroke work index. More specifically, only the indices, which include the area inscribed in the pressure-strain loop correlated with invasive measurements, that is GWI, GCW, GPW, and GSCW. In fact, each of these indices includes the broader slice of stroke work, namely shortening during the ejection phase. This is not surprising, since invasively calculated work is only stroke work, that is the area inscribed in the pressure-volume loop. Correlation index has reached the highest value with the combination of GWI and GCW, therefore combining two indices could provide more reliable insights into myocardial function. In addition, ROC curves generated to assess predictive performance of significantly correlated STE-derivate indices for LV SWI have shown great areas under the curve, above all GCW, which confirmed itself as the MW index more affine to SWI.All other myocardial work indices which have not shown a correlation with invasive measurement take into account different aspects of the mechanics and energetics of heart. For instance, GWW and GSWW focus on the work performed by some myocardial segments in the wrong moment of the cardiac cycle, such as lengthening in systole and shortening in diastole. On the contrary, GWE represents an index and for this reason is conceptually different from calculation of work with the invasive method.However, even though results have shown some degree of correlation between GWI, GCW, GPW, and GSCW with SWI, “r values” are not high enough to support a robust correlation from a statistical point of view. One of the main reasons for which correlation indices were not so high is probably the fact that echocardiographic exams and RHC were not performed on the same day in all cases. It is widely known that these patients suffer from rapid hemodynamic variations indeed.This study also correlated invasive measurement of work with traditional echocardiographic indices of systolic function, particularly EF and GLS. Even though such indices are conceptually different from work, they also evaluate systolic performance of heart. It is of particular interest the fact that, from EF to MW indices passing through GLS, correlation indices and statistical significance progressively increased. This means that, among the whole range of echocardiographic indices for the evaluation of systolic function available nowadays, newer ones perform better.Aside from understanding whether these novel indices are reliable or not as compared to invasive measures, one of the key elements toward which future studies should point is how they could be integrated in clinical practice and at what extent they could enhance patients’ management. As a matter of fact, as patients with AHF often need careful clinic visits comprehensive of echocardiogram examination at close time intervals, more sensible advanced parameters of left ventricular systolic function should be implemented to better characterize disease progression and optimize referral for advanced therapies, such as HTX, not to miss the golden window. Since an invasive evaluation strategy with RHC at each time point is inapplicable, a non-invasive evaluation could potentially complement the hemodynamic evaluation at shorter time intervals.This study was a single-center and retrospective analysis. The main limitations of the study include: the enrolled patients are part of a restricted population of subjects with AHF, which limits the extent of the results to the general population. However, since correlation has been performed between measurements with the two methods in the same individual, this should be of limited concern. Time between echocardiographic exam and right heart catheterization was very low, but not null in all cases. Since these particular patients suffer from rapid hemodynamic variations, even few weeks could be potentially relevant. Nonetheless, if this was true, correlation could only be underestimated. The number of patients in which correlation analysis was performed is relatively low. However, considering the invasive nature of catheterization, this was sufficient for the purpose of the study. If it was not, results would not have reached statistical significance.Speckle tracking echocardiography-derived LV MW allows to non-invasively assess the work performed by the heart during a cardiac cycle. This study demonstrated a significant correlation between some MW indices and invasive measurement of LV stroke work derived from RHC in a cohort of patients with AHF considered for heart transplantation, therefore potentially representing a powerful tool for a more comprehensive evaluation of myocardial function.The raw data supporting the conclusions of this article will be made available by the authors, with adequate motivation.The studies involving human participants were reviewed and approved by Comitato Etico Regione Toscana Area Vasta Sud Est. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.FL, GEM, and MC conceived and designed the study protocol and wrote the manuscript. FL, BC, MB, GM, GD, and CS participated in the acquisition of data. FL performed statistical analysis. ML, FF, FD’A, MFo, MFi, AI, SB, MM, and SV revised the manuscript and participated in the interpretation of results. All authors gave the final approval of the manuscript version to be submitted.