Objectives: Heart rate turbulence (HRT) and T-wave alternans (TWA), non-invasive markers of cardiac autonomic dysfunction, and ventricular repolarization abnormality, reportedly, predict the risk of cardiovascular death after myocardial infarction. We investigated whether pre-operative assessment of HRT and/or TWA could predict long-term mortality following coronary artery bypass graft (CABG) surgery. Methods: From May 2010 to December 2017, patients undergoing elective CABG and receiving 24 h ambulatory electrocardiogram monitoring 1 to 5 days prior to CABG surgery were prospectively enrolled. Pre-operative HRT and TWA were measured using a 24 h ambulatory electrocardiogram. The relative risk of cardiac or overall death was assessed according to abnormalities of HRT, TWA, or left ventricular ejection fraction (LV EF). Results: During the mean follow-up period of 4.6 Conclusions: Assessment of pre-operative HRT and/or TWA predicted mortality risk in patients undergoing elective CABG. Combined analysis of HRT, TWA, and LVEF enhanced the prognostic power. In particular, the predictive value of HRT was enhanced in patients with preserved or mid-range LV EF. Coronary artery bypass graft (CABG) surgery has been established as the treatment of choice for myocardial revascularization in patients with severe coronary artery disease (CAD) ,2. HowevTherefore, more accurate risk stratification and better management of patients treated by CABG are critical in clinical practice. Left ventricular (LV) ejection fraction (EF) is the most widely used prognosis parameter after CABG surgery ,5. HowevHeart rate turbulence (HRT) and T-wave alternans (TWA), non-invasive electrocardiographic markers reflecting cardiac autonomic dysfunction and ventricular repolarization abnormality, respectively, have been shown to predict the risk of cardiovascular or SCD in patients with ischemic or non-ischemic cardiomyopathy ,11,12,13Therefore, we investigated whether pre-operative abnormal HRT or TWA could predict post-CABG mortality using a prospective CABG registry. We also evaluated the prognostic value of the non-invasive parameters alone or in combination with LV EF. This was a prospective, single-center, observational registry study. We included consecutive patients who underwent elective CABG surgery with CAD, including acute or chronic coronary syndrome, and who received 24 h ambulatory electrocardiogram monitoring 1 to 5 days prior to CABG surgery from May 2010 to December 2017.Inclusion criteria for the present study were as follows: (1) age ≥ 18 years; (2) CABG based on current guidelines; and (3) pre-CABG Holter recording for at least 20 h. Exclusion criteria for the present study were as follows: (1) urgent/emergent surgery prohibiting pre-operative 24 h electrocardiogram monitoring; (2) inadequate Holter recording for assessment of HRT or TWA; (3) pre-existing  AF; and (4) ventricular paced rhythm. This study was approved by the Institutional Review Board (IRB) of Samsung Medical Center in the Republic of Korea (IRB number: 2010-04-050). All patients provided informed consent.The recording and analysis of ambulatory electrograms have been described previously . In brieAll surgeries were performed via standard median sternotomy. At our hospital, off-pump CABG via the bilateral internal thoracic arteries is the preferred technique. The internal thoracic artery was used as the main graft, and other vessels such as the great saphenous vein were used if needed. The type of surgery and treatment strategies including the number of grafts used and administration of medication after CABG were determined by the experienced surgeon. Aspirin or warfarin was started within the first 24 h after surgery and beta blockers, calcium channel blockers, renin–angiotensin system blocker, or anti-arrhythmic agents were used during the postoperative period when clinically indicated. We prospectively collected basic demographic data, past medical and medication history, 12-lead electrocardiographic and echocardiographic data, type or extent of coronary artery disease, and surgery-related data. The medication data was collected during the period of 24 h ambulatory electrocardiogram monitoring before CABG surgery. The primary outcome of this study was cardiac death including sudden cardiac death and all-cause death. Patients were regularly followed up in the outpatient clinic for at least 1 year  or through telephone interviews when patients did not visit the clinic at the scheduled time . Masked p-values < 0.05 were considered statistically significant. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) software, version 27.0 . Continuous variables are expressed as median with interquartile range, and categorical variables are presented as count and percentage and were compared by the Mann–Whitney test and Fisher’s exact test. Event rate curves were obtained using a Kaplan–Meier analysis and were compared using the log-rank test. The risks for the outcomes were assessed using a Cox proportional hazards model and are presented as adjusted hazard ratio (HR) with a 95% confidence interval (CI) for age, sex, medication use of beta blocker and renin–angiotensin system blocker, QRS duration, numbers of PVCs, and acute (vs. chronic) coronary syndrome. To assess the sensitivity and specificity of each parameter and to define the cut-off points that maximized the separation of outcome analysis, receiver operating characteristic analysis was performed. A total of 146 patients  and 5 cardiac deaths (event rate 0.9%/yr) occurred during the mean follow-up duration of 4.6 RT group . In contRT group . A worseRT group . AdditioRT group . The accuracy values were higher for a combination of abnormal HRT, abnormal TWA, and LV EF < 50% . All parameters showed high specificity and negative predictive values .The subgroup analysis was performed according to baseline LV EF . Incidence rates of all-cause death were 6.53%, 5.91%, and 5.79% per year in the severely reduced, mid-range, and preserved EF groups, respectively. Abnormal HRT with/without abnormal TWA played no significant role in predicting all-cause death in the severely reduced EF group . However, the predictive value of abnormal HRT with/without abnormal TWA regarding all-cause mortality became evident in the mid-range  and preserved EF groups  .This study investigated the predictive value of pre-operative ambulatory ECG-based non-invasive parameters for serious outcomes after elective CABG surgery in CAD patients during a mean follow-up period longer than 4 years. Abnormal HRT measured within 5 days prior to surgery predicted hard outcomes during long-term follow-up. The combination of abnormal HRT, abnormal TWA, and impaired EF improved the predictive value up to 9 fold for all-cause death and 87 fold for cardiac death. This predictive value was particularly significant in patients with preserved or mid-range LV systolic function. Furthermore, the negative predictive value of HRT was high enough to predict cardiac death. The accuracy goes higher when analyzing combined parameters including abnormal HRT, abnormal TWA, and abnormal LV function compared to single each parameter. Severe LV systolic dysfunction is the most powerful prognostic factor for cardiovascular or SCD in patients with ischemic or non-ischemic cardiomyopathy, for whom an implantable cardioverter defibrillator (ICD) is recommended by the current guidelines to reduce the risk of mortality . HoweverHRT, a surrogate marker of cardiac autonomic dysfunction, has been proposed as a useful non-invasive prognostic marker for mortality in patients with MI ,18. HRT Previously, clinical implications of HRT and/or TWA were validated mostly in patients with reduced LV systolic function ,13,14,15In our study result, the negative predictive value of combined parameters including abnormal HRT plus abnormal TWA plus LV EF < 50% was high, especially in cardiac death (98%). The positive predictive value of combined parameters showed low in both outcomes. The accuracy was higher when analyzing with combined parameters than a single parameter alone. These results are similar to previous studies ,20. The Recently, the utilization of single- or multi-channel wearable devices for ambulatory electrocardiographic monitoring has gained unprecedented interest from physicians and patients ,23. VariThe optimal time for HRT measurement is not definitive; serial testing has shown that non-invasive tests beyond 8 weeks after MI reliably identify patients at risk of serious events. The REFINE study reported that the combination of impaired HRT and TWA measured at 10 to 14 weeks post-MI can predict hard outcomes in patients with impaired LV systolic function . HoweverThis study was a prospective observational study, but the sample size and number of events, particularly cardiac deaths, were small. Assessment of HRT is limited to patients with sinus rhythm and VPC with certain VPC characteristics and R-R patterns. Therefore, some patients were excluded from the final analysis. The lower cardiac event rate may be related to complete revascularization therapy with CABG of most patients with preserved baseline LV systolic function. To overcome this limitation, we observed patients for a long period of time and analyzed all-cause mortality as well. Also, this study missed other risk stratification algorithms such as the European System for Cardiac Operative Risk Evaluation (EuroSCORE), which is a cardiac risk model for predicting mortality after cardiac surgery. In addition, the risk of SCD was not assessed due to the low event rate. Therefore, additional studies with a larger scale should be conducted to validate the clinical implications of HRT and/or TWA for risk stratification of arrhythmic or SCD in patients undergoing CABG surgery.Pre-operative measurement of HRT and/or TWA was likely useful in risk stratification of mortality in patients undergoing elective CABG. In particular, the predictive value was significant in patients with preserved or mid-range reduced LV EF. Additionally, the combined analysis of HRT, TWA, and LV EF improved the prognostic power. These parameters might be used for screening the high-risk population for cardiac adverse outcomes. Further, a larger-scale trial is necessary to confirm the clinical implications.


ST-segment elevation myocardial infarction (STEMI) still causes significant mortality and morbidity despite best-practice revascularization and adjunct medical strategies. Within the STEMI population, there is a spectrum of higher and lower risk patients with respect to major adverse cardiovascular and cerebral events (MACCE) or re-hospitalization due to heart failure. Myocardial and systemic metabolic disorders modulate patient risk in STEMI. Systematic cardiocirculatory and metabolic phenotyping to assess the bidirectional interaction of cardiac and systemic metabolism in myocardial ischemia is lacking.Systemic organ communication in STEMI (SYSTEMI) is an all-comer open-end prospective study in STEMI patients > 18 years of age to assess the interaction of cardiac and systemic metabolism in STEMI by systematically collecting data on a regional and systemic level. Primary endpoint will be myocardial function, left ventricular remodelling, myocardial texture and coronary patency at 6 month after STEMI. Secondary endpoint will be all-cause death, MACCE, and re-hospitalisation due to heart failure or revascularisation assessed 12 month after STEMI. The objective of SYSTEMI is to identify metabolic systemic and myocardial master switches that determine primary and secondary endpoints. In SYSTEMI 150–200 patients are expected to be recruited per year. Patient data will be collected at the index event, within 24 h, 5 days as well as 6 and 12 months after STEMI. Data acquisition will be performed in multilayer approaches. Myocardial function will be assessed by using serial cardiac imaging with cineventriculography, echocardiography and cardiovascular magnetic resonance. Myocardial metabolism will be analysed by multi-nuclei magnetic resonance spectroscopy. Systemic metabolism will be approached by serial liquid biopsies and analysed with respect to glucose and lipid metabolism as well as oxygen transport. In summary, SYSTEMI enables a comprehensive data analysis on the levels of organ structure and function alongside hemodynamic, genomic and transcriptomic information to assess cardiac and systemic metabolism.SYSTEMI aims to identify novel metabolic patterns and master-switches in the interaction of cardiac and systemic metabolism to improve diagnostic and therapeutic algorithms in myocardial ischemia for patient-risk assessment and tailored therapy.Trial Registration Number: NCT03539133The online version contains supplementary material available at 10.1186/s12872-023-03210-1. ST-segment elevation myocardial infarction (STEMI) continues to confer a substantial burden of morbidity and mortality with plateauing numbers since 2008 , 2. Lateobjective of the present cohort study  is to identify metabolic systemic and myocardial master switches that determine outcomes after STEMI. The aims are as follows: (i) to characterize myocardial and systemic metabolism in STEMI together with early regional LV function, LV remodeling, myocardial texture and infarct characteristics at index hospitalization (ii) to characterize the interaction of systemic and myocardial master switches using unsupervised cluster analysis to identify patients with a specific metabolic risk phenotype at index hospitalization (iii) to identify novel therapeutic master switches and networks prone to interventions and modulations.The www.clinicaltrials.gov: NCT03539133. SYSTEMI will recruit patients at the academic main-hospital of Heinrich Heine University Düsseldorf, Germany with > 150 STEMI per year, as well as in secondary pPCI -centres within the academic network of Heinrich Heine University Düsseldorf (“Heart-net”), Germany with > 80 STEMI per year. To optimize recruitment efficacy, training sessions have been performed with the interventional staff on call and the study nurses to best inform the patients about the study dependent examinations during their guideline directed diagnostics and therapy at index hospitalisation. As shown in the study flow . Ethics approval was given by the local ethics committees  complying with the Declaration of Helsinki under reference numbers 5961R and 2,021,055. SYSTEMI is registered at According to our all-comer design, all patients referred to our hospital with a STEMI diagnosis will be asked for informed consent, if no exclusion criterion is present. The main exclusion criteria are age < 18 years, living abroad, and a life-limiting disease with a life expectancy of < 1 year or an unfavourable neurologic outcome. Patients who meet the exclusion criteria will be enrolled in a parallel STEMI register.Patient selection and short informed consenting will be done by the physician on call at the coronary care unit immediately before the start of pPCI. Before the final consent is given, the investigator or his/her representative will explain verbally the aim, method, source of funding, and the anticipated benefits and potential risks to the participants and answer all questions regarding the study. As part of the general informed consent, all screening subjects are being asked for serial collection of blood samples and its storage in a biobank as well as further genetic analysis. Biosamle processing and storage is done according to existing standard operating procedures (SOPs) at -80 °C. Biosample access is regulated by the SOPs and granted by standardized evaluation upon formal request. Apart from liquid specimen, electronic patient data are collected systematically and online within the Duesseldof Outcome, Safety and Risk Assessment Registry (DOSAR) via health level (HL)-7 interfaces connected to clinical data systems. All requirements of the General Data Protection Regulation are met. A unique participant number will be allocated to each participant (pseudonymization) and assigned chronologically prior to proceeding with study screening. The sequential identification numbers will be used to collect, store, and report participant information.2 for oxygen consumption. In parallel, the first liquid biopsies will be generated. The liquid biopsies will serve for assessing basic laboratory parameters including lactate to assess cardiogenic shock and biobanking specimen aiming at subsequent cellular, biochemical, immunological and genetic analyses. Guideline directed repetitive ECG recordings and monitoring will be conducted (V1).The detailed study protocol is given in SPIRIT Table Within the first and third day after reperfusion we will conduct additional cardiac imaging with transthoracic echocardiography and in a subset of patients cardiovascular magnetic resonance (CMR)  including measurements of ventricular mass, volume, function and myocardial relaxometry (V2 + V4). Cine imaging will be used to calculate pressure-volume curves by taking phase-to-phase volumes of short-axis slices, blood pressure and left ventricular end-diastolic pressure measurements from acute catheterization measurements . Additio1 H and 31P-MRS, which are key techniques for measuring fatty acids (FA) and total creatine as well as ATP, Pi and pH, will be integrated into the clinical CMR protocol 5 days and 6 months after STEMI. For 1 H-MRS, navigator-free metabolite-cycled spectroscopy using a voxel size of approximately 4–6 ml (10 × 15 × 35 mm3) and ≈ 144 averages (7:50 min) will be applied [31P spectra. Reconstruction will be performed using a customized reconstruction pipeline in ReconFrame . jMRUI/AMARES will also be used to analyze MR spectra. Simultaneously, we will have information through liquid biopsies on the diabetes endotype in patients with overt diabetes and on glucose tolerance in patients without diabetes by applying oral glucose tolerance test (OGTT). To asses circulatory adaptations of large conductive arteries, we will apply pulse wave velocity measurements by 4-dimensional velocity-encoding in CMR and by carotid-femoral applanation tonometry using Sphygmocor® technology . The central aortic blood pressure, pulse pressure (PP) and augmentation index (AIX) will be assessed. To assess the primary endpoints, that is LV function, LV remodeling, LV metabolism, LV texture and coronary patency, after complete myocardial healing at 6 months after STEMI, we scheduled further examinations (V7). These examinations comprise of a coronary angiography, echocardiography, CMR, OGTT, applanation tonometry and additional liquid biopsies. The secondary endpoints will be assessed by a telephone call at 12 months (PC8). Further observational phone calls (PC9-11) are planned on a yearly basis.During V2-V5 we will additionally empower the patients to stick to the study by providing detailed information about his health status and study specific examination results. Five days after pPCI (V6), we will again apply echocardiography and CMR with the addition of magnetic resonance spectroscopy (MRS). For regional myocardial metabolic profiling,  applied . jMRUI/AThe SYSTEMI Steering Committee is responsible for the scientific content of the protocol, oversees the study steps, and checks adherence to “Good Clinical Practice” and the study protocol as well as performance. Study conduction will follow the SOP of the Clinical Trial Unit (CTU) of the University Hospital of Düsseldorf. The SYSTEMI Endpoint Adjudication Committee (EAC) will adjudicate clinical endpoints based on data provided by the clinical trial sites. This procedure will be supervised by the trial coordination center  at Heinrich Heine University. The trial management committee (TMC) meets once a week and the steering committee twice a year to review trial conduct. The data monitoring committee (DMC) consist of a data manager and participants of the external advisory board. Patient data are collected systematically and online within the DOSAR Registry via health level (HL)-7 interfaces connected to clinical data systems. All requirements of the General Data Protection Regulation are met. The DMC will report in a weekly manner organizational aspects of data collection and handling as well as quality and completeness reports. Data quality and completeness is of prime importance in SYSTEMI. Regular audits are conducted synchronized to the annual meeting of the Cardiovascular Research Institute Düsseldorf (CARID). Upon formal request according to our internal SOP, access to primary data can be given. This process is guided by the SYSTEMI Steering Committee, which is responsible for the scientific content of the study data.SYSTEMI was designed as open-end prospective cohort study in all comer STEMI patients. No formal sample size calculation has been performed. It was anticipated that more than 160 STEMI patients per year will be a realistic recruitment speed on the basis of expected STEMI patients at host institutions to reach a total sample size of > 1000 STEMI patients.This cohort study was designed to unravel novel master switches and markers of metabolic networks in STEMI patients to further facilitate risk stratification and identify novel therapeutic targets in STEMI. For primary endpoints, logistic regression analysis will be used to model the predefined outcome data with impact of covariates. The effects of the independent parameters in these regression models will be estimated  and presented with 95% confidence intervals. Network analysis using machine learning approaches for unsupervised metabolic cluster identification will be conducted. Secondary endpoint analysis will be performed using Kaplan–Meier plots and the log-rank test. Two-tailed p values below 0.05 will be considered indicative of statistically significant differences. Since significant interactions of master switches within the metabolic network are anticipated, interim analysis will be done after 500 and 1000 patients for a robust statistical power calculation and re-adjustment of investigations.Mortality and morbidity after STEMI remain high and current risk prediction models do not take metabolic risk constellations into account. Therefore, the overall objective of SYSTEMI is to identify systemic and myocardial metabolic master switches that determine outcomes after STEMI. To reach this objective, we have designed and set-up SYSTEMI to comprehensively investigate systemic and myocardial metabolism at index hospitalization and at 6 months in more than 1000 patients. SYSTEMI will enable in-depth analyses of systemic metabolic effectors on local myocardial function and metabolism, as detected by magnetic resonance imaging and spectroscopy, and clinical outcome.2 transport capacity of the blood. The first metabolic cluster covers the glucometabolic spectrum of hyperglycemia, hyperinsulinemia, and insulin resistance to T2DM and the role of specific endotypes of T2DM in patients with STEMI. Altered glucose metabolism can be seen in up to 50% of all STEMI patients, but only 25% remain in this state after 3 months [To our knowledge, the present cohort study is the first study in patients with STEMI to systematically and simultaneously assess organ-function, inter-organ communication as well as myocardial and systemic metabolism. SYSTEMI focuses on 3 metabolic clusters: (i) the glucometabolic spectrum, (ii) the lipid metabolism and (iii) the O3 months . Moreove3 months . Therefo3 months , 14. In 3 months , 14. Thi3 months . The sec3 months , the lip3 months  on infar3 months . Anemia 3 months . This ap1 H- and 31P-MRS measurements by reducing the scan time or voxel size for examining metabolism in infarcted and remote zones [1 H-MRS may estimate myocardial triglyceride and total creatine levels, whereas 31P-MRS is able to quantify metabolites such as phosphocreatine, ATP, their ratio or creatine kinase fluxes [1 H- and 31P-MRS. In perspective, myocardial metabolism will be further assessed by use of hyperpolarized 13 C-substrates, such as pyruvate, bicarbonate or lactate, combined with advanced deuterium metabolic imaging [To enable comprehensive investigation of the bidirectional interaction of systemic and cardiac metabolism through the aforementioned pathways in the acute phase of STEMI and its long-term outcome in patients, several layers of analysis have to be accomplished within SYSTEMI: (i) analysis of cardiac and circulatory function prior to and immediately after pPCI, on the 1st, 3rd, and 5th day of the index hospitalization using novel CMR techniques, (ii) assessment of glucose and lipid metabolism, and (iii) readouts of various organ and tissue functions during and after STEMI, including the liver, the pancreas, the spleen, and circulating blood and immune cells arising from bone marrow, the kidney, skeletal muscle, and adipose tissue. This is complemented by targeted multiomics analysis, including proteomics, lipidomics, and long-read sequencing, and novel CMR-based techniques to study myocardial flux rates and energy metabolism in mice and patients. In perspective, SYSTEMI seeks to link regional functional and structural alterations with local myocardial metabolism. Several technical improvements in recent years have facilitated the application of MRS, te zones . In expee fluxes . Current imaging .SYSTEMI aims to identify individuals with distinct susceptibility to myocardial ischemia among the different endotypes of T2DM across the glucometabolic spectrum, endotypes of anemia and lipid disorders, paving the way for precision medicine in STEMI and cardiometabolic disorders.Below is the link to the electronic supplementary material.Additional File Table 1: CMR sequences used and respective references


Although staging of the extent of aortic stenosis (AS)-related cardiac damages is usually performed via echocardiography, this technique has considerable limitations in assessing pulmonary artery and right chamber pressures. The present hypothesis-generating study sought to explore the efficacy of a staging system of cardiac damage based on echocardiographic and invasive [right heart catheterization (RHC)] hemodynamic parameters in patients undergoing transcatheter aortic valve implantation (TAVI).2 and a right atrial pressure of >10 mmHg.We studied 90 symptomatic patients with severe AS in whom echocardiographic and invasive evaluation by RHC was obtained prior to TAVI. Cardiac damage stages were defined as follows: no cardiac damage (stage 0), left ventricular (LV) damage (stage 1), left atrial or mitral valve damage (stage 2), pulmonary vasculature or tricuspid valve damage (stage 3), and right ventricular (RV) dysfunction or low-flow state (stage 4). With the integrative approach using RHC, pulmonary hypertension (PH) was defined as an mPAP ≥25 mmHg and the low-flow state corresponded to a cardiac index of <1.8 L/min/mDuring follow-up (median: 2.9 years), 43 patients (47.8%) died. The integrative cardiac damage staging was associated with a significant increase in all-cause and cardiovascular mortality per each increase of cardiac damage stage, whereas the outcome was similar according to the echocardiographic staging.A staging system of cardiac lesion based on echocardiographic and invasive hemodynamic parameters in patients with severe AS undergoing TAVI predicts mortality. Patients with pre-existing PH, ≥ moderate tricuspid regurgitation and/or RV dysfunction, and a low-flow state had a markedly increased risk of death. Further larger studies are needed to validate our findings. Current2.2.1.We conducted a retrospective analysis of systematically collected data of symptomatic patients with severe AS who underwent TAVI and who had RHC within 1 month prior to intervention in our Heart Valve Center  between October 2016 and January 2020. A total of 139 symptomatic patients were screened during the study period. After the exclusion of patients who underwent valve-in-valve TAVI procedure, patients with moderate to severe mitral stenosis, patients with incomplete echocardiographic or RHC data, and patients who lacked follow-up information, the final analysis consisted of 90 patients . Baselin2.2.RHC was performed with a 7Fr Swan–Ganz catheter by femoral access. Right atrial pressure, systolic (sPAP), diastolic, and mean (mPAP) pulmonary arterial pressure and pulmonary capillary wedge pressure were measured. Cardiac output was estimated through the thermodilution method. From these data, we derived pulmonary vascular resistance [(mPAP—pulmonary capillary wedge pressure)/cardiac output], cardiac index (cardiac output/body surface area), and stroke volume index (cardiac index/heart rate). PH was defined and classified according to the 2015 European guidelines, which was the existing recommendations on PH at the time the study was conducted .2.3.Transthoracic echocardiography with a Vivid 95 GE machine was performed by a cardiologist with high experience in valvular heart disease assessment. Echocardiographic images were analyzed using the EchoPac software v204 . The presence of severe AS, the chambers dimensions, LV and RV function, and valvular regurgitation evaluation were defined according to the current guidelines . LV dias2.4.-2 for women, >115 g/m2 for men), and/or LV diastolic dysfunction ≥ grade 2 and/or LV systolic dysfunction (LV ejection fraction <60%); stage 2, left atrial and/or mitral valve damage: left atrial enlargement (left atrium volume index >34 ml/m2) and/or ≥ moderate mitral regurgitation, and/or atrial fibrillation; stage 3, pulmonary vasculature or tricuspid valve damage: PH defined as sPAP ≥ 60 mmHg, and/or ≥ moderate tricuspid regurgitation; stage 4, RV damage and/or subclinical heart failure: RV dysfunction based on a multiparametric evaluation  and/or low-flow state (stroke volume index <30 ml/m2).The echocardiographic staging was based on the one proposed by Tastet et al. : stage 0-2 and right atrial pressure >10 mmHg).In the integrative cardiac damage staging, the definitions of PH and of low-flow state were based on RHC data: stages 0,1, and 2 were assessed by echocardiography as aforementioned, whereas stages 3 and 4 were assessed integrating the data from RHC: stage 3: PH was defined by a mPAP ≥ 25 mmHg at RHC, and/or ≥ moderate tricuspid regurgitation on echocardiography; stage 4: RV dysfunction  and/or low-flow state, defined at RHC by cardiac index <1.8 L/min/mThe patients were categorized into five stages according to the extent of extra-aortic valve cardiac damage based solely on echocardiographic data (the echocardiographic staging) or based on combined echocardiographic and RHC data (the integrative staging) :-The ecIn both classifications, the patients were hierarchically classified in a given stage (worst stage) if at least one of the proposed criteria was satisfied. Given the small number of patients observed in stages 0–1, we described our population by merging stages 0–1–2, corresponding to left-chamber cardiac damage.2.5.After TAVI, the patients were routinely followed-up and managed according to the available guidelines. Clinical endpoints were obtained from medical reports. Primary outcome was all-cause death. Secondary outcomes were the occurrence of cardiovascular death, stroke, myocardial infarction, and heart failure hospitalization.2.6.https://www.R-project.org/), and a p-value < 0.05 was considered statistically significant.Qualitative variables are presented as count and percentage and comparisons were performed by chi-square test or Fisher exact test when appropriate. Quantitative variables are presented as mean ± SD, and comparisons were performed by ANOVA test. To compare the survival function of different cardiac damage stage, the time-to-event data Kaplan–Meier plots and log-rank test were used. A pair-wise comparison between group levels for log-rank test was conducted with corrections for multiple testing using the Benjamini–Hochberg methods. To investigate the independent association between mortality and the new staging classification, univariable and multivariable Cox proportional hazards model were developed and adjusted for age, New York Heart Association (NYHA) class, chronic kidney disease, diabetes, history of atrial fibrillation, and peak aortic valve velocity according to significance in univariable analysis or as known risk factor. All statistical analyses were performed two-sided with SAS 9.4  and R . Female represented 55.6% of the total population, and no significant gender differences were present between groups (p = 0.01), while in the integrative staging, stages 3 and 4 had a similar percentage of patients in NYHA class III/IV .n groups . Most ofIntra-procedural and post-procedural characteristics of the patients are reported in 3.2.2, LV ejection fraction 54.7 ± 10.7%, stroke volume index 42.3 ± 9.6 ml/m2, peak aortic valve velocity 4.2 ± 0.7 m/s, aortic mean gradient 45.9 ± 15.0 mmHg, and aortic valve area 0.75 ± 0.16 cm2. In both staging classifications, the stage 4 patients had lower systolic blood pressure, possibly related to their low-flow state.Baseline pre-TAVI echocardiographic data for the entire population and according to the stage of cardiac involvement are summarized in p = 0.02), stroke volume index , and peak aortic velocity . As expected, the stage 4 patients more often had RV dilatation and dysfunction according to both staging classifications. Stages 3 and 4 were also associated with larger left atrial volumes, significant mitral and tricuspid regurgitations, and higher sPAP.In comparison with the patients in stages 0–2 or stage 3 in the echocardiographic staging system, the patients in stage 4 had significantly lower LV ejection fraction  and stroke volume index  were observed across all the spectrum of stages.The baseline invasive data for the overall population and according to the stage of cardiac injury are summarized in 2 in stages 0–2, 2.8 ± 0.8 L/min/m2 in stage 3, 2.5 ± 0.6 L/min/m2 in stage 4, p < 0.01, and stroke volume index 41.5 ± 9.5 ml/m2 in stages 0–2, 39.3 ± 6.2 ml/m2 in stage 3, 35.8 ± 9.2 ml/m2 in stage 4, p = 0.02). As expected, the integrative staging was the only one able to show differences between groups in terms of pulmonary vascular resistance .As expected, the use of RHC led to an increase in the identification of patients with PH in comparison with echocardiography, which translates into three times higher number of patients in stage 3 seen in the integrative staging as compared with the echocardiography staging system. Intriguingly, echocardiography was able to accurately identify the patients in low-flow state as well as the invasive method (cardiac index 2.9 ± 0.6 L/min/m3.4.p = 0.02) and cardiovascular death  across all stages. The echocardiographic staging showed higher and comparable all-cause mortality and cardiovascular mortality in stages 3 and 4 . Other MACE  and NYHA functional class III/IV showed no difference between the two groups in both staging models.The clinical outcomes for the entire population and by stages are summarized in 3.5.p < 0.01). Stage 4 showed a significantly lower survival probability compared with stages 0–2  and stage 3 . On the contrary, stage 3 did not show a significantly lower survival probability compared with stages 0–2 . The intersection of the curves of stages 0–2 and 3 was likely related to the small number of patients present after the 4-year follow-up. The echocardiographic staging (p = 0.44).The Kaplan–Meier curve analysis of the integrative staging  showed a staging  of our c3.6.p < 0.01] after adjustment for several variables known for their clinical relevance (p = 0.43).In a multivariable Cox survival model, the integrative staging emerged as a strong independent predictor of all-cause mortality for each stage increase [adjusted hazard ratio (HR): 1.69; 95% confidence interval 1.16–2.44; elevance . In cont4.To the best of our knowledge, this is the first study to evaluate an AS staging integrating both echocardiographic and invasive parameters in a cohort of patients with severe symptomatic AS undergoing TAVI. In the present study, in the integrative cardiac damage staging, there was a gradual increase in all-cause and cardiovascular mortality per each increase of cardiac damage stage, whereas in the echocardiographic staging, stages 3 and 4 had similar mortality rates. Analyzing the Kaplan–Meier curves, the integrative stage 4 showed a significantly lower survival probability compared with stages 0–2 and 3. Also, the new proposed integrative staging has shown to be a predictor for all-cause death in multivariable analysis, above and beyond several clinical factors known to have a negative prognostic impact. On the other hand, in our study, the echocardiographic staging was not correlated with all-cause or cardiovascular mortality. Therefore, we can hypothesize that the integrative staging might allow for better individual risk stratification as compared with the conventional echocardiographic staging model. These results reinforce the interest of using the RHC in the workup of patients with advanced AS.4.1.Recently, an echocardiographic staging classification, including 4–5 stages, has been proposed and validated to assess and report the extent of cardiac damage associated with AS. A gradual increase in mortality was observed for each stage increment in symptomatic patients with severe AS undergoing AVR, as well as in asymptomatic patients with moderate or severe AS. Advanced stages were associated with a marked increase in the short-term risk of mortality both before and after AVR . In theiOur study strongly supports the use of RHC for the evaluation of cardiac damage and provides additional data on the importance of further examining the upstream repercussions of AS on the pulmonary circulation and the right ventricle. We found that a high proportion of patients undergoing TAVI had PH (46%) or RV dysfunction (39%), and these patients were at high risk for adverse outcomes. With the integrative approach, the gradual increase in mortality for each stage was more pronounced compared with the conventional echocardiographic approach. The risk of death was even more marked in stage 4 when the variables were analyzed as a function of time. The two staging classifications differed mainly by a greater number of patients with definite PH and a better characterization of patients with a low-flow state using RHC data.Although a possible explanation for the lack of correlation between the echocardiographic staging system and outcome in our study as opposed to the previously mentioned studies could be related to the low number of patients included in our study, the use of RHC could prove to be useful for the evaluation of these patients. RHC represents the gold standard for measuring pulmonary pressures, defining and classifying PH , and forThe definition of PH in the echocardiographic staging systems is only based on an sPAP ≥ 60 mmHg –8. As su4.2.With the aging of the population and the advent of TAVI as a treatment option, clinicians are increasingly confronted with patients presenting with long-standing AS, multimorbidity, progressive RV dysfunction, and pulmonary vascular disease. Although operative mortality is increased in cases of severe PH, the benefit provided by surgical AVR is undoubtedly greater than conservative management . However4.3.First, the number of patients examined was relatively low, especially with initial stages 0–1, which is why they were logically grouped with stage 2, corresponding to left-chamber cardiac involvement. However, there are relatively few published data on invasive hemodynamics collected systematically from real-life patients with AS before TAVI. Second, echocardiography and RHC were not performed simultaneously. Nonetheless, they were both done within the month of the TAVI procedure, and we do not expect the cardiac stage to change in such a short time. Third, the staging classification was assessed in patients with severe AS treated by TAVI. Therefore, we did not assess the impact of the extent of cardiac damage during the natural course of AS.4.4.Staging of extra-valvular cardiac damage using both echocardiographic and invasive parameters was independently associated with a progressive increase in adverse outcomes following TAVI for severe AS. This integrative staging might allow for better individual risk stratification compared with the conventional echocardiographic staging model. Future prospective studies are needed to assess the additional value of this integrative cardiac damage staging system during the natural course of AS.


Changes in LVEF corresponded with significant differences in NT proBNP trajectories, but initial biomarker levels or clinical staging were not predictive of LVEF trajectory. Conclusions: in ATTR-CM patients with impaired LVEF, over a third demonstrated improved LVEF over time, while those with a decrease in LVEF had worse long-term outcomes.Background: Transthyretin cardiac amyloidosis (ATTR-CM) is classically thought of as a progressive disease with preserved systolic function. The longitudinal clinical trajectories of ATTR-CM with impaired left ventricular ejection fraction (LVEF) remain unclear. Methods: This is a single-center retrospective cohort study of consecutive patients with ATTR-CM who underwent two or more echocardiograms with baseline LVEF < 50%. Patients were stratified according to the presence of ≥5% change in LVEF. A Cox proportional hazard model examined hazard of a composite outcome of death, transplant, or LVAD insertion over the two years following diagnosis. Results: In our study cohort of 179 patients, 62 patients (34.6%) experienced an increase in LVEF while 33 (18.4%) experienced a decrease in LVEF. After adjusting for covariates, patients with a decrease in EF experienced increased hazard of death (HR 2.15, 95% CI 1.05–4.40,  Cardiac amyloidosis (CA) is characterized by the extracellular deposition of amyloid fibrils in the heart, with the distinctive histological property of green birefringence when viewed under cross-polarized light microscopy after staining with Congo red. There are two main types of CA, namely transthyretin (TTR) cardiomyopathy (ATTR-CM) and light chain (AL) cardiomyopathy (AL-CM) . In ATTRTransthyretin amyloid cardiomyopathy (ATTR-CM) was previously considered a rare disease, but now has a growing recognition as a potential treatable cause of heart failure (HF), especially in older adults . AlthougThe latest American College of Cardiology/American Heart Association clinical guidelines in the management of heart failure have provided new recommendations regarding the diagnosis and treatment of ATTR-CM. Specifically, patients with ATTR-CM presenting with HFmrEF/HFrEF should cautiously follow general recommendations of initiating guideline-directed medical therapy, despite little prospective evidence to guide management . Given tWe included consecutive ATTR-CM patients with HFrEF (defined as LVEF ≤ 40% using the Simpson’s Biplane Method) or mildly reduced ejection fraction  seen at a tertiary care hospital system between 1 January 2008 and 31 May 2021 with available serial echocardiographic evaluations performed. The protocol was approved by our Institutional Review Board as a retrospective study that waived informed consent. ATTR-CM patients over age 18 years with either HFrEF or HFmrEF were considered under the umbrella of HF with abnormal LVEF (HFmrEF/HFrEF). Diagnosis of ATTR-CM was established via endomyocardial biopsy or with 99mTc-PYP scanning with single-photon positron emission computerized tomography (SPECT)/computed tomography (CT). A 99mTc-PYP was considered positive based on a heart to contralateral ratio of 1.3 or greater at 3 h and myocardial uptake grade 2 or 3. Patients were confirmed to have ATTR-CM through the appropriate exclusion of light chain (AL) amyloidosis based on standard guideline-based criteria. Demographic, clinical characteristic, imaging, and laboratory data were obtained at the initial clinical encounter. Baseline LVEF was adjudicated from echocardiogram performed closest to the time of diagnosis within 90 days of the initial clinical encounter [p value < 0.05 was considered statistically significant.Data were expressed as medians (interquartile ranges (IQR)) given non-normal distributions and proportions where appropriate. Between-group comparisons of baseline comparisons were performed using the chi-squared test or Fisher Exact testing as appropriate for categorical variables and Kruskal–Wallis testing for continuous variables. Time to event was visualized using Kaplan–Meier curves, and group differences were tested with the Log-rank test. Cox proportional hazard models were then used to examine hazard of death, transplant, or left ventricular assist device (LVAD) following diagnosis with ATTR-CM. Penalized smoothing (p) splines were used to account for nonlinear relationships between covariates and hazard. Schoenfeld testing was performed to validate that the proportional hazards assumption was maintained. Survival comparisons were performed across groups and adjusted for race, NT-proBNP, cardiac troponin-T, baseline LVEF, and coronary artery disease. Statistical analyses were performed using R Studio Statistical Software version 1.2.5033 , and p = 0.613).In our contemporary cohort of 262 consecutive patients with ATTR-CM and systolic dysfunction (165 with HFrEF/97 with HFmrEF), 179 had sequential echocardiograms performed with median duration of 12.4 months between echocardiograms. We observed that 62 patients (34.6%) demonstrated improvement in LVEF, 84 patients (46%) had stable or unchanged LVEF, and 33 patients (18.4%) experienced worsened LVEF over the first year following their baseline assessment . For thop-value of 0.021. After adjusting for covariates, patients with a reduction in LVEF experienced worse outcomes compared to those with stable or increased in LVEF over a five-year follow-up period   . In our single-center retrospective cohort in tertiary referral center, we observed that over a third of ATTR-CM patients with HFmrEF or HFrEF experienced unchanged or increased LVEF over time, and had better outcomes than those with a decrease in LVEF over time. There were no specific baseline clinical characteristics that were associated with a greater likelihood of increase in LVEF over time. Taken together, we observed that the stability or improvement of left ventricular function portends a better prognosis than those whose LVEF declines after adjusting for key clinical prognostic variables. Transthyretin amyloid cardiomyopathy is classically described as a form of HFpEF with adverse cardiac remodeling because of progressive amyloid fibril deposition, leading to cardiac hypertrophy and diastolic dysfunction, restrictive cardiomyopathy, and ultimately systolic dysfunction as a harbinger of advanced disease that is presumably irreversible . Our cenAlthough the role of guideline-directed medical therapy in ATTR-CM is still debated, the fact that some patients improve their LV function with medical management is encouraging and merits further study ,8. The eWhether this reverse remodeling is secondary to the implementation of disease-modifying therapies for systolic heart failure or adjustments in loop and thiazide diuretics leading to adequate decongestion is unclear based on these results. The study period mostly pre-dates the advent of contemporary-guideline-directed medical therapy (GDMT) medications, which includes angiotensin receptor/neprilysin inhibitor and sodium-glucose co-transporter 2 inhibitors; therefore, further investigation into the impact of contemporary GDMT on ATTR-CM is needed ,10. FutuThe significant differences in natriuretic peptide trajectories and their association with prognosis and LV recovery suggests a potential role for natriuretic peptides not only with the initial staging of ATTR-CM, but also in the ongoing assessment of clinical trajectory, including the presence of positive remodeling . In contLimitations: Our single-center retrospective cohort in a tertiary referral center is limited by the expected selection and referral biases that may impact a larger-than-expected proportion of HFrEF presentation. Patients also had varying time intervals of clinical follow-up evaluations and incomplete availability and timing of repeat echocardiograms and biomarkers. While this analysis showed prognostic associations with systolic function over time and the ability of amyloid ventricles to recover function, it did not provide further insight into which patients are likely to experience improvement or deterioration in LVEF. Whether this is reflective of the genotype, volume optimization, medical therapy use, burden of amyloid deposition, acuity of presentation, or other factors should be the subject of further study.An increase in LVEF is observed in over a third of ATTR-CM patients with systolic dysfunction within the first year. Those who experienced decrease in LVEF had a two-fold increased hazard of worse long-term outcomes than those with increased or unchanged LVEF, suggesting potential insights for medical management and longitudinal risk stratification in ATTR-CM with systolic dysfunction. Future studies should prospectively address the role of contemporary GDMT in the clinical outcomes of patients living with ATTR-CM.


Sarcoidosis is a rare cause of cardiomyopathy that can easily be confused for acute heart failure when pulmonary manifestations are absent. We present the case of a 41-year-old female presenting with dyspnea found to have ventricular arrhythmia on arrival at the emergency department. Cardiac magnetic resonance and computed tomography of the chest with contrast were performed, confirming the systemic sarcoidosis diagnosis with cardiac involvement. Sarcoidosis is a multisystem inflammatory disease of unknown etiology, characterized by noncaseating granulomas in various organs . More thA 41-year-old female with a past medical history of hypertension presented with sudden palpitations, shortness of breath, and diaphoresis shortly after attending a car racing event where she was consuming alcohol. On admission to the emergency department, she was found to have a heart rate of 219 bpm with stable blood pressure and slight dyspnea. Otherwise, she was hemodynamically stable with an unremarkable physical exam. Her labs showed a 0.06 ng/mL troponin, Brain natriuretic peptide (BNP) of 432 pg/mL, and normal electrolytes. Her initial electrocardiogram (ECG) showed a wide-complex tachycardia with a rate of 250 bpm  with aberrancy. The underlying ECG rhythm showed a right bundle branch block (RBBB) pattern and some left atrial (LA) enlargement Figure . Her cheOn further questioning, the patient reported recently having three pillow orthopnea and dyspnea on exertion. A transthoracic echocardiogram showed an ejection fraction of 30-35%, a mildly dilated left ventricular (LV) cavity, hypokinesis of the basal anterior and anteroseptal segments the LV, stage 2 diastolic dysfunction, a mildly dilated LA, and a normal RV. Given her initial presentation and concern for heart failure, the medical team decided to pursue left heart catheterization for possible obstructive coronary artery disease (CAD), the results of which revealed no vascular disease. Given an unclear diagnosis with findings of heart failure, a computed tomography (CT) of the chest with contrast was completed. It showed innumerable sub-centimeter nodules in a perilymphatic distribution Figure . Given tGiven the constellation of findings, there was a concern for systemic sarcoidosis with cardiac involvement. A fludeoxyglucose (FDG) positron emission tomography (PET) was unavailable in the inpatient setting. As per cardiology consult recommendations, the patient subsequently had magnetic resonance imaging (MRI) of cardiac morphology and function with delayed gadolinium, which showed patchy abnormal mid-myocardial delayed enhancement in the left ventricular myocardium Figure -8. This We present a case of what initially appeared to be an arrhythmia related to new-onset heart failure, presenting with cardiac symptoms without outward evidence of sarcoidosis involvement in other organ systems . On further investigation, however, imaging revealed perilymphatic nodules and lesions throughout the spleen and liver consistent with sarcoidosis. True isolated CS is rare , and its existence itself is controversial, as sarcoidosis is, by definition, a systemic disease . Recent Though 20-25% of patients with pulmonary or systemic sarcoidosis are estimated to have some cardiac involvement, only about 5% will develop clinically manifest cardiac features ,7. IndeeCommon presenting features of clinically manifest CS include conduction abnormalities like AV block, ventricular arrhythmia (VA), and heart failure, consistent with our patient's presentation . Even inCS should be suspected when dyspnea appears disproportionate to the degree of apparent lung involvement. An initial baseline ECG is recommended in all sarcoidosis patients and may reveal ventricular atopy, left or right bundle branch block, pathologic Q waves, or ventricular arrhythmia. The recommended work-up includes a transthoracic echocardiogram and cardiac MRI or PET CT if MRI is unavailable/ineffective or when renal dysfunction precludes Gadolinium contrast agents . MRI andThough difficult, diagnosis of CS can be accomplished through one of two ways: 1. a histological diagnosis from myocardial tissue, or 2. clinical diagnosis after negative myocardial biopsy . The latter requires at least one or more of the following: steroid +/- immunosuppressant responsive cardiomyopathy or heart block, unexplained reduced LV ejection fraction (<40%), unexplained sustained (spontaneous or induced) ventricular tachycardia, Mobitz type II second-degree heart block or third-degree heart block, patchy uptake on dedicated cardiac PET, late gadolinium enhancement on cardiac MRI, positive gallium uptake, and reasonable exclusion of other causes for cardiac manifestations.The first-line treatment for CS is corticosteroid therapy, which may improve survival but has not shown a reduction in the incidence of VA . ICD plaThe diagnosis of CS is challenging, mainly when presenting with symptoms of heart failure without pulmonary manifestations. As demonstrated in our case, patients with CS are at elevated risk of ventricular arrhythmias, which are also more difficult to predict. In presenting this case study, we hope to encourage early clinical suspicion for CS in cases of arrhythmia by highlighting the high incidence of VA in this clinically variable condition.


P < .01). Statistically, excellent agreement was obtained between the clinical and robotic test-retest results of the scale (P < .01) . There was a statistically significant positive correlation between the clinical and robotic device results of the Modified Ashworth Scale . There was a statistically significant positive correlation between the hand strength values measured with the robotic device, Jamar grip, pinch, and Fugl-Meyer Assessment Hand Subscale scores (P < .01) in the patient group. Hand finger spasticity and strength measurements of the Amadeo hand-finger robotic rehabilitation system were valid, reliable, and clinically correlated in stroke patients.We aimed to investigate the validity, reliability, and clinical relevance of Amadeo hand-finger robotic rehabilitation system measurements for evaluating spasticity and strength in hemiplegic patients. In total, 161 participants  were included in this study. Spasticity was evaluated using the Modified Ashworth Scale, hand motor functions were evaluated using the Fugl-Meyer Assessment Hand Subscale, and hand grip and pinch strength were evaluated using the Jamar hand grip and pinch dynamometer. The Amadeo (Tyromotion) hand-finger robotic rehabilitation system was used to evaluate finger spasticity and strength of the participants. A statistically significant difference was found between the median values of the Modified Ashworth Scale  and the mean values of hand flexor and extensor strength measured with the robotic device in patients compared to healthy subjects ( Spasticity is a common complication experienced by 19% to 43% of stroke survivors. The high prevalence of spasticity and limited effectiveness of existing treatment options highlight its significance as a major health problem in neurological rehabilitation.Stroke is the second leading cause of disability and death worldwide. A validated scoring system should be used in the clinical evaluation of spasticity to ensure quantification. The Ashworth Scale (AS) or Modified Ashworth Scale (MAS) are the most frequently employed scales, which measure passive resistance at the joint as perceived by the examiner hence, giving rise to qualitative and subjective data. Most of these scales have major limitations in terms of reliability and inter-rater reproducibility. Owing to differences in clinical background and training, the assessment of spasticity may vary among clinicians, and the evaluation process can also depend on various subtle factors. Furthermore, the time-consuming nature of these assessments may discourage their frequent use in monitoring and evaluating motor recovery.Spasticity management relies on clinical patient assessment. Substantial evidence has shown that robotic systems can be beneficial in rehabilitating people with disabilities. Furthermore, these robotic devices can be used to evaluate upper extremity function during treatment. Spasticity can also be integrated into robotic assessment protocols by considering its effect on the speed and direction of movement of the upper extremity. Robotic devices are thought to have advantages, such as being monitored in every rehabilitation session (even during each movement), emphasizing even small changes, early detection of the healing plateau, and reduction of evaluation bias for spasticity assessment. Although many studies have utilized robotic and other objective measures, their reliability and validity still need to be established to the same extent as clinical scales. Moreover, the relationship between robotic measurements and clinical scales remains largely unknown. To the best of our knowledge, only one study in the literature has evaluated finger spasticity using a hand-finger robot. In this study, it was concluded that the strength measurements correlated with the clinical results, but the test-retest reliability of the spasticity measurements was weak.Robot-aided therapy devices are equipped with sensors and built-in technology that enable the automatic measurement of motion kinematics and kinetics, providing an opportunity to assess the patient’s condition.In this study, we aimed to investigate the validity, reliability, and clinical relevance of Amadeo hand-finger robotic rehabilitation system measurements for evaluating spasticity and strength in our stroke patient population.Patients aged 40 to 85 years, with a history of stroke at least before 6 weeks, who were admitted to the Afyonkarahisar Health Sciences University, Department of Physical Medicine and Rehabilitation between February 15, 2022, and February 15, 2023, were included. The exclusion criteria were an open wound on the hand, acute orthopedic injury, visual impairment that prevents seeing the screen, advanced cognitive impairment, contracture in the wrist and/or fingers, or grade 4 spasticity in finger flexors according to MAS staging. Among these, 107 stroke patients who met the inclusion criteria were included  by the Afyonkarahisar Health Sciences University, Clinical Research Ethics Committee. The study was also registered at ClinicalTrials.gov (identifier number NCT05662878). All participants provided written informed consent in accordance with the principles outlined in the Declaration of Helsinki. During the assessment of spasticity, the patients were in a sitting and relaxed position, and the examiner moved the joint at 3 different speeds: V1 (slow), V2 (speed of gravity), and V3 (as fast as possible) to be comparable to robotic device measurements and assigned a rating of resistance on a scale of 0 to 4 ; 1+ = slightly increased resistance ; 2 = clear resistance throughout most of the range of motion; 3 = strong resistance; passive movement is difficult; 4 = rigid flexion or extension).,14 For the statistical analysis of MAS values, 1 + values were recorded as 2, 2, 3, and 3 as 4.An investigator blinded to other clinical measures and robotic assessments performed the clinical assessment of spasticity twice daily at different times using MAS. MAS is one of the most widely used scales in the clinical field because it is easy to apply, does not require special equipment, and can be quickly applied. The FMA-UE scale includes 7 types of hand assessment movements, including grip, pinch, and coordination of fingers (FMA-hand). Each movement was assigned a qualitative rating with a score of 0, 1, or 2, depending on how well it was performed. In this study, we evaluated the hand functions of the participants using the 7-item FMA-Hand subscale.The motor functions of the patients were evaluated clinically using the Fugl-Meyer Assessment for the Upper Extremity (FMA-UE). The Fugl-Meyer Assessment of Upper Extremity (FMA-UE) is a well-established and widely used scale developed to assess and quantify the extent of post-stroke sensorimotor recovery in the upper extremity. It is considered a valid and reliable tool.Hand grip strength was measured clinically using a Jamar dynamometer. Finger lateral pinch strength was evaluated using a Jamar digital pinch meter. Measurements were made with the shoulder adjacent to the trunk in adduction and neutral rotation, the elbow in 90° of flexion, the wrist in 0–30° of dorsiflexion, and the ulna in 0°–15° of ulnar deviation with the thumbs up. The patients were asked to squeeze with maximum force, 3 measurements were taken, and the averages were recorded.Robotic Assessments were performed by a researcher experienced in robotic rehabilitation, trained in using the device, and blinded to the patient’s clinical findings and previous evaluation results. The Amadeo  hand-finger robotic rehabilitation system was used for robotic evaluation of the participants. This is an end-effector device that helps one or all 5 fingers flex and extend independently in a horizontal plane. The robot is not affected by the anatomical limitations of joint alignment owing to its degrees of freedom, and it measures the multi-joint movements of the fingers. The sensors transmitted simultaneous movement information to a computer screen during rehabilitation. Synchronous finger movements are shown in 5 columns. Before the test, the investigator warned the participants about the association to relax their fingers. Spasticity (three repetitions) and muscle strength (three repetitions) were evaluated during the tests to prevent the onset of spasticity due to the maximum contractions that may occur during the evaluation. The same investigator assessed each participant in 2 sessions using the passive ROM recorded in the initial assessment  evaluation. Next, the fingers were moved through the entire passive ROM at 3 different speeds: V1 (slow), V2 (medium), and V3 (fast). Velocities are configured such that all fingers initiate and reach their destination simultaneously   analysis for test and retest reliability with the G Power package program, the total number of individuals included in the study was a minimum of 158 for alpha 0.05 and beta 0.20 (80% power).U test was used to compare groups for variables that did not follow a normal distribution. Categorical data were compared between groups using Fisher exact test and Pearson’s chi-square test, and multiple comparisons were adjusted using Bonferroni correction. Spearman’s rank correlation coefficient was used to evaluate the relationships between variables that did not follow a normal distribution. Agreement between the 2 assessments was evaluated using the ICC. Descriptive statistics, such as frequency (percentage), mean ± standard deviation, and median (minimum-maximum), were used for categorical and quantitative variables. Statistical significance was set at P < .05.Data were analyzed using the IBM SPSS V23 software. The normality of the distribution was checked using the Shapiro–Wilk test. The Mann–Whitney P = .07). At the same time, the median age in the patient group was 65 years, and 63 years in the healthy group. The median time after stroke in the patient group was 8 (2–97) months. The affected extremities were on the right side in 45.8% (n = 49) and the left side in 54.2% (n = 58). There was no difference between the patient and control groups in terms of sex, occupation, or dominant hand distribution (P > .05) , 49.1% (n = 79) were male, and 50.9% were female (n = 82). There was no statistically significant difference between the median ages of the groups  in the patients and healthy subjects (P < .01). In addition, excellent agreement was obtained between the robotic device test-retest results of the MAS in the patient group   Table .r = .72; P < .01). In addition, there was a statistically significant positive correlation between the hand flexor strength values measured with the robotic device, Jamar grip and pinch, and FMA-Hand scores (P < .01). There was a statistically significant negative correlation between MAS score and other clinical evaluations (P < .01)  Table .This study examined the validity and reliability of spasticity and strength measurements using the Amadeo hand finger robotic rehabilitation system in patients with stroke. Our findings show that robotic measurements are reliable and compatible with clinical scales. In a pilot study evaluating the spasticity of 5 patients before and after botulinum toxin administration using an upper extremity robotic device, it was concluded that an exoskeleton robotic device named the NEEM could show even small changes in spasticity. Dehem et al reported that spasticity measurements of 12 stroke patients using the upper extremity robotic device ReaPlan after the motor block procedure correlated with MAS measurements. To the best of our knowledge, only one study has evaluated the spasticity level of finger flexors using a robotic device; Amadeo was used in this study. Germanotta et al reported differences in MAS scores conducted with Amadeo between patients and healthy subjects. Additionally, the reliability of the measurements was poor and did not show a significant correlation with the clinical scale. In contrast to this study, we found that the measurements were reliable and correlated with the clinical scales. Germanotta et al attributed the weak reliability of the results to the low MAS values in the sample and the small variability of MAS in the sample. Germanotta et al included patients in the subacute period (<6 months after stroke). Unlike the study by Germanotta et al, we included patients in the chronic phase. We believe that we obtained a reliable result with a wider MAS distribution of the patients in our study.Centen et al utilized a robotic exoskeleton to evaluate spasticity at the elbow and reported within-class correlations ranging from 0.66 to 0.95 on mechanical measurements. Studies have suggested that muscle weakness has a greater effect on grasping strategies than spasticity. Therefore, the evaluation and rehabilitation of finger strength are as important as those of spasticity. ICCs were found between 0.85 and 0.99 in studies investigating the test-retest reproducibility of the Jamar dynamometer, which is frequently used in the evaluation of hand grip strength in stroke patients.–23 For this reason, we evaluated the correlation of our robotic muscle strength measurements with Jamar dynamometer results and the Fugl-Meyer Assessment, the most widely used method to evaluate motor function in stroke patients. A strong positive correlation was observed between the Jamar grip strength measurements and FMA-Hand scores and the finger flexor strength values obtained with the robotic device. Germanotta et al evaluated strength using Modified Research Council (MRC) measurements and found that Amadeo hand strength measurements were in excellent agreement with MRC. In addition, in our study, a significant difference was found between the mean strength of the finger flexors and extensors measured with Amadeo in the patient and healthy groups. All these results show that finger strength measurements measured with Amadeo can distinguish patients from healthy individuals and are compatible with clinical scales.Finger grip strength is associated with motor function and activities of daily living.Dynamometers measuring grip strength were used to measure hand strength. However, as it is known, it is difficult to evaluate muscle strength in stroke patients, especially in patients who do not have hand grip function in the early stages. Although grip is known to be an important function, testing the muscle strength and voluntary flexion movement that will create the grip provides the opportunity to observe the patient in more detail in the early stages of rehabilitation. Robotic devices can measure patients’ active ROM percentages and provide measurements of isolated finger flexion-extension strength. Our study showed that hand flexion strength measured using robotic devices correlated with dynamometer measurements. It was also compatible with the Fugl-Meyer Assessment Hand subscale, which evaluates motor function. In this context, we believe that mechanical muscle strength and spasticity measurements can provide fast, easy-to-apply, reliable, and detailed measurements during the hand rehabilitation process of stroke patients.The fact that robotic devices, which have begun to be used in treatment practice, can also be used in the evaluation of patients may provide ease of application. In addition, it will provide a chance to avoid the problem of different interpretations between evaluators, which may arise from personal experience and skills. Robotic measurements of spasticity and finger strength are reliable and compatible with clinical scales. Our results will contribute to the literature because there are limited studies in the literature that evaluate finger spasticity and strength using robotic devices. Further studies are needed to determine the current reliability of the measurements of various robotic devices used in rehabilitation practice.A limitation of this study is that we should have examined the inter-rater reliability. However, this limitation does not significantly affect our results because robotic evaluation is not dependent on the practitioner, and the reliability of manual evaluations has been studied previously.Hand finger spasticity and strength measurements of the Amadeo hand-finger robotic rehabilitation system are valid, reliable, and clinically correlated in stroke patients. Robotic spasticity and strength measurements can be used in clinical evaluations to guide treatment plans.Conceptualization: Sevda Adar, Ali Demircan, Ali İzzet Akçin, Ümit Dündar, Hasan Toktaş, Hilal Yeşil, Selma Eroğlu, Nuran Eyvaz, Ersin Beştaş, Cansu Köseoğlu Toksoy.Data curation: Sevda Adar, Ali Demircan, Ali İzzet Akçin, Nuran Eyvaz, Cansu Köseoğlu Toksoy.Formal analysis: Sevda Adar, Hilal Yeşil, Selma Eroğlu, Nuran Eyvaz.Investigation: Sevda Adar, Ali Demircan, Ali İzzet Akçin, Ümit Dündar, Hasan Toktaş, Hilal Yeşil, Selma Eroğlu, Nuran Eyvaz, Ersin Beştaş, Cansu Köseoğlu Toksoy.Methodology: Sevda Adar, Ümit Dündar, Hasan Toktaş.Project administration: Sevda Adar, Ali İzzet Akçin.Resources: Sevda Adar, Ali Demircan, Ali İzzet Akçin, Ümit Dündar, Hasan Toktaş, Hilal Yeşil, Selma Eroğlu, Nuran Eyvaz, Ersin Beştaş, Cansu Köseoğlu Toksoy.Software: Sevda Adar.Validation: Sevda Adar, Hilal Yeşil, Selma Eroğlu.Visualization: Sevda Adar, Ali Demircan, Ali İzzet Akçin.Writing – original draft: Sevda Adar.Writing – review & editing: Sevda Adar, Ali Demircan, Ali İzzet Akçin, Ümit Dündar, Hasan Toktaş, Hilal Yeşil, Selma Eroğlu, Nuran Eyvaz, Ersin Beştaş, Cansu Köseoğlu Toksoy.


Most guidelines directing clinicians to manage valve disease are directed at single valve lesions. Limited data exists to direct our understanding of how concomitant valve disease impacts the left ventricle (LV).We identified 2817 patients with aortic stenosis (AS) from the echocardiography laboratory database between September 2012 and June 2018 who had a LV ejection fraction (EF) ≥50%. LV mass, LV mass index, LV systolic pressure (systolic blood pressure + peak aortic gradient). Covariates were collected from the electronic medical record. Multi‐variate analysis of covariance was used to generate adjusted comparisons.p < .001 vs. p = .313, respectively) at all levels of adjustment. Both significant mitral and AR exhibited an association with increasing left ventricular mass, even with adjustment for baseline demographics and clinical features .Our population was 66% female, 17% African‐American with a mean age of 65 years. Of note, 7.3% were noted to have significant (moderate/severe) aortic regurgitation (AR), and 11% had significant (moderate/severe) mitral regurgitation (MR). Adjusting for covariates at different levels, significant MR had a much stronger association with heart failure compared to those with significant AR (In patients with AS, 16% also experience at least moderate MR or AR. Further, significant MR has a stronger association with heart failure than significant AR, even though both increase left ventricular mass. Those with moderate AS and significant MR or AR experience similar or higher levels of heart failure compared to severe AS without regurgitation. Mixed valve disease merits further studies to direct longitudinal management. In addition, the natural history of mixed valvular disease is not well known.2The Wake Forest University School of Medicine Institutional Review Board (IRB) reviewed and approved this research study. With this being a retrospective study of data obtained during routine clinical care, the IRB granted a waiver of informed consent. After obtaining Institutional Review Board approval, patients shown to have mild, moderate, or severe AS with a preserved left ventricular ejection fraction (EF) >50% were identified in the Wake Forest School of Medicine echocardiography database. Those with a left ventricular EF <50% were excluded because of the difficulty in accurately assessing the degree of AS in that population. Between September 2012 and June 2018, a total of 2817 patients were identified with reports that included the above parameters, and these clinical cases comprised the study population. Clinical and demographic data were extracted from the electronic medical records.2.1The echocardiographic measurements included left ventricular dimensions, left ventricular ejection fraction , the transvalvular gradients as determined by the simplified Bernoulli equation, and aortic valve area using the continuity equation.2.22, moderate AS was defined as an AVA 1.0–1.5 cm2, and mild AS was defined as an AVA >1.5 cm2.Doppler echocardiography data were used to categorize patients by aortic valve disease severity. Severe AS was defined as an AVA ≤1.0 cm2.3Valvular regurgitation was assessed according to the American Society of Echocardiography (ASE) valvular regurgitation guidelines and classified by one of our clinical echocardiographic faculty as reflected in their finalized echocardiogram report.2.4Heart failure was captured by identifying those who were diagnosed with heart failure by a healthcare provider in their past medical history in the electronic medical record.2.5Results were expressed as mean ± SD or percentages. Differences between patient groups were analyzed using ANOVA for continuous variables, and the chi‐square test or Fisher's exact test for categorical variables, as appropriate. All statistical analyses were performed using SAS JMP 16.1 To adjust for covariates, a graded model‐based approach was employed. For the relationship between left ventricular mass and AS as defined by AVA, an ANCOVA approach was used. Model I adjusted for AR, MR, body surface area, and peak aortic valve systolic pressure gradient, and Model II performed further adjustment for age, race, and sex. For model III, additional adjustments were made for clinical variables, such as coronary artery disease, hypertension, diabetes mellitus, and chronic kidney disease.For the relationship between heart failure and AS as defined by AVA, a logistic regression approach was used. Model I adjusted for AR, MR, body surface area, and peak aortic valve systolic pressure gradient, and Model II performed further adjustment for age, race, and sex. For model III, additional adjustments were made for clinical variables, such as coronary artery disease, hypertension, diabetes mellitus, and chronic kidney disease.3After excluding those with a left ventricular EF less than 50%, prosthetic valves, endocarditis, or missing data, our study population consisted of 2817 patients with AS. Their characteristics by AS severity are shown in Table p < .0.001 vs. p = .313, respectively; Table In unadjusted analyses, increasing AR was not statistically associated with increasing heart failure in those with severe AS, but for those with moderate AS, those with AR experienced a similar or higher prevalence of heart failure relative to those with severe AS without regurgitation . As for left atrial remodeling, those with significant MR across all levels of AS saw increased left atrial volume index (p < .001), but in those with significant AR, only those who had severe AS experienced a relative increase in left atrial volume index (p = .050).In evaluating the potential association between valvular regurgitation and further remodeling in those with AS, both increasing aortic and MR were associated with a higher left ventricular mass index relative to those without regurgitation  half of patients with AS have mixed valve disease; 16% of those with AS have at least moderate aortic or MR; (2) increasing MR has a stronger association with clinical heart failure in those with AS than those with concomitant AS and regurgitation; (3) both significant mitral and AR increase left ventricular mass in those with AS; (4) patients with moderate AS and moderate or severe MR experience higher levels of heart failure than severe AS without regurgitation.Several pathways exist to potentially explain why heart failure was more prevalent in those with significant MR as opposed to those with significant AR. First, the presence of significant MR may be an indicator of more severe AS—the hemodynamics of which has contributed to progressive dysfunction of the mitral valve itself.In spite of MR having a stronger association with heart failure, both increasing mitral and AR were associated with higher left ventricular mass. Both lead to progressive left ventricular dilation from volume overload, which eventually results in clinical heart failure.Using severe AS without any regurgitation as the standard, multiple mixed valve dysfunctions experienced similar or higher levels of heart failure. Notably, in those with moderate AS, those who also had any degree of MR experienced higher prevalence of heart failure compared to those with severe AS without regurgitation. For those with AR and moderate AS, they experienced similar rates of heart failure as those with severe AS without regurgitation, and those with moderate AS and severe regurgitation experienced even higher levels of heart failure. These observations invite several questions: (1) if a particular mixed valve combination experiences a higher degree of heart failure than isolated severe AS, should we be intervening in some of these situations sooner than what we presently are?Inherent with all studies, our approach possesses limitations that should be referenced when considering our findings and conclusions. First, the echo data were derived from the clinical database of a clinical‐active tertiary referral center with a significant amount of variation in study quality, interpretation, and data reported. This approach presents several notable challenges, including quantitative classification of valvular regurgitation. While many of the echocardiographers used vena contracta, PISA, and deceleration time to evaluate regurgitation severity, because it was not entered as a measurement, we were unable to capture that information. Second, the clinical data derived from our clinical data repository from the electronic medical record represents the clinical opinion of many providers, and therefore, the clinical data lacks the precise, reproducible and accurate classification that would have resulted from prospective data judged by an adjudication committee with tight, validated clinical definitions. This most significantly impacts the data concerning heart failure where the limited documentation prevents us from being more specific and granular in our analyses and conclusions. As a crude validation, the medication use for those with heart failure are presented (see Table 5In patients with aortic stenosis, nearly half have mixed valve disease with 16% having at least moderate mitral or aortic regurgitation. Further, significant mitral regurgitation has a stronger association with heart failure than significant AR, even though both increase left ventricular mass. Those with moderate aortic stenosis and significant mitral or AR experience similar or higher levels of heart failure compared to severe aortic stenosis without regurgitation. Mixed valve disease merits further studies to direct longitudinal management.None.


Background: Type 2 sodium-glucose cotransporter inhibitors (SGLT2i) are among the main therapeutic options for patients with chronic heart failure with reduced ejection fraction (HFrEF). The aim of this study was to evaluate the effects of SGLT2i on the echocardiographic parameters of left (LV) and right (RV) ventricular function among outpatients with a long history of HFrEF, in optimized therapy. Methods: We evaluated consecutive patients affected by HFrEF in whom the SGLT2i therapy was prescribed. Following a baseline evaluation (T0), in which SGLT2i was prescribed, patients were re-evaluated at 3 (T3), 6 (T6), and 12 (T12) months. Results: We considered 60 patients for the analysis with a median history of HFrEF of more than seven years in optimal medical and electrical therapy. After SGLT2i therapy, LV ejection fraction and LV global longitudinal strain improved from baseline at T3, T6, and T12. Analogously, RV global and free wall longitudinal strain improved at T3 and T6. Conclusions: Our study shows that the addition of SGLT2i to the optimized therapy for HFrEF was associated with a significant improvement in both LV and RV function, thus highlighting a possible mechanism responsible for the benefit obtained with this class of drugs. Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) have been demonstrated to significantly improve the outcome of patients affected by chronic heart failure (CHF) with reduced ejection fraction (HFrEF) ,2. They In a retrospective study with a longer follow-up, an improvement in left ventricular (LV) function was observed, but only in patients affected by T2DM . In diabThis study aimed to evaluate the 12-month effects of SGLT2i on the echocardiographic parameters of both LV and RV function among diabetic and non-diabetic outpatients with a long history of HFrEF and optimized therapy.The enrolled patients were all referred to the heart failure unit of the University Policlinic Hospital of Foggia for HFrEF. They were selected from the Daunia registry, a single-center observational registry, which also aimed to prospectively evaluate the effects of new therapeutic approaches on clinical and echocardiographic parameters. Local ethics committees approved the registry, and all enrolled patients provided written informed consent.All patients to whom therapy with SGLT2i was prescribed were considered. Following the requirements of the Italian Ministry of Health, we enrolled patients to whom dapagliflozin (since February 2022) or empagliflozin (since June 2022) could be prescribed and reimbursed by the National Health System, i.e., with New York Heart Association (NYHA) class II–III, left ventricular ejection fraction (LVEF) ≤ 40%, already treated, if not contraindicated or not tolerated, with ACE-inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) or sacubitril/valsartan, mineralocorticoid receptor antagonists (MRA), and beta-blockers . PatientPatients with a recent diagnosis of heart failure and those without optimal treatment in the last six months were excluded. Patients with atrial fibrillation and irregular rhythm and those with poor quality echocardiographic imaging were also excluded due to the limitations in assessing ventricular function by two-dimensional speckle tracking (2D-ST) analysis.Baseline evaluation (T0) was considered the evaluation before SGLT2i were started. Every effort was made to repeat the baseline evaluations at 3 (T3), 6 (T6), and 12 (T12) months. Moreover, evaluations conducted between 6 and 12 months before initiating SGLT2 inhibitor therapy (T-6/12) were analyzed when available.-Medical visit and ECG: history of ischemic heart disease, arterial hypertension, diabetes mellitus, estimated glomerular filtration rate (GFR), NYHA class, arterial pressure, and rhythm and heart rate at ECG were recorded. The dose of heart failure classes of drugs was evaluated as follows: for ACEi, the equivalent enalapril dose was calculated according to the following proportions: enalapril 20 mg/day equivalent to ramipril 10 mg/day, zofenopril 30 mg/day, and lisinopril 20 mg/day. For ARBs, the equivalent valsartan dose was calculated according to the following proportions: valsartan 320 mg/day equivalent to losartan 100 mg/day, and candesartan 32 mg/day [-Echocardiographic examinations. Echocardiographic examinations were analyzed by two operators  who were in the blind from the time of the evaluation as well as from the results of the other examinations of each patient. In accordance with current recommendations, LVEF was calculated on the basis of left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) (Simpson’s rule). The ratio between E and e′ (E/e′) was based on the peak of the E wave (E) at pulsed Doppler and the TDI peak of early diastolic velocity peak (e′) at the level of the septal and lateral mitral annulus . Mitral At each time, the following evaluations were performed:t-test, whereas dichotomized variables by Fisher’s test. In order to assess the relationship between the variables, Pearson’s linear correlations were used. The linear mixed model for repeated measurements was used to test differences among the values observed at each evaluation, i.e., T-6/12, T0, T3, T6, and T12. Statistical analyses were performed using STATA software, Version 12  or Statistica 6.1 software . A p value of <0.05 was considered statistically significant.Statistical analysis. The continuous variables are expressed as mean values ± SD. Continuous variables were compared by Student’s Out of 78 patients, 18 were excluded, nine because they had a recent history of HFrEF, seven because of atrial fibrillation with irregular rhythm, and two because of non-adherence and early withdrawal of SGLT2i therapy . The cliIn order to evaluate the changes in the studied echocardiographic variables before the enrollment, for 43 patients, a comparison between baseline evaluation and those available from 6 to 12 months before baseline was performed. No significant differences were found in LVEDV (mean relative change −1.1 ± 14.1%), LVEF (mean relative change −3.2 ± 16.9%), LV-GLS (mean relative change +3.7 ± 20.5%); MR (mean relative change −0.4 ± 36.5%); LAVI (mean relative change +14.9 ± 53.4%); E/e′ (mean relative change +11.2 ± 48.1%); TAPSE (mean relative change −3.9 ± 15.7%); RV-GLS (mean relative change: +8.7 ± 32.1%); RV-fwLS (mean relative change: +7.3 ± 30.3%); and TR (mean relative change: −11.5% ± 37.1%).All enrolled patients repeated baseline evaluations at least once at 3 months (T3) or 6 months (T6). T3 was available in 53 patients and T6 in 54. In 48 patients, it was also available at 12 months (T12). The serial analysis of LVEF and LV-GLS was available for all patients, whereas RV strain measurements were available in only 53 patients due to the quality of imaging. p < 0.001) and relative changes in RV-GLS , but not with those in RV-fwLS . Relative changes in RV-GLS were significantly correlated with absolute changes in LVEF  and relative changes in RV-fwLS . No correlations were found between changes in LAVI and E/e′ and those observed for LVEF and LV-GLS. Relative changes in E/e′ were significantly correlated with improvements in RV-GLS  and TAPSE .When all changes from baseline were analyzed, relative changes in LV-GLS were significantly correlated with relative changes in LVEF , RV-fwLS (58%), and RV-GLS (60%).The main finding of this study is that, in diabetic and non-diabetic HFrEF patients receiving the recommended therapy, SGLT2i can improve both RV and LV functions, as assessed by conventional parameters and 2D-ST during a 1-year follow-up. An improvement in both LV and RV function was already observed in previous studies. Indeed, a recent metanalysis demonstrated the relationship between SGLT2i and an improvement in LV, but not in RV function. Mustapic et al. ,16, in aConsequently, our study adds new evidence about the possible effects of SGLT2i. We enrolled patients with HFrEF and a long history of heart failure who had already received optimal medical or electrical therapy for at least six months. Notably, 98% of patients were taking beta-blockers, 85% received MRA, 22% underwent CRT, and a significant percentage were on ACEi/ARB and sacubitril/valsartan. These therapies maximize reverse cardiac remodeling and improve LVEF when combined ,22. TherThese findings further support the hypothesis that SGLT2i exert their effects through complementary mechanisms, with an additive effect when combined with other recommended drugs ,23. ThisThese multifaceted effects highlight the complex and promising nature of SGLT2i in heart failure management and can explain the improvements in both LV and RV function that we observed. This last finding is relevant from a pathophysiological and clinical point of view. RV function could play a relevant role in the progression of heart failure. Many studies have demonstrated the independent and incremental prognostic relevance of an impaired RV function. However, as of today, there are no specific therapeutic approaches for enhancing RV function . The impThe results of our study about the beneficial effects of SGLT2i on both LV and RV systolic function are further reinforced by the analysis of 2D-ST derived parameters. 2D-ST provides information about segmental and global myocardial deformation. In particular, in recent years, longitudinal strain analysis has demonstrated greater sensitivity in detecting early myocardial dysfunction compared to traditional echocardiographic parameters . MoreoveIn our series, the evaluation of natriuretic peptides was not available for all patients. This is a very relevant point to better clarify the pathophysiological mechanisms underlying the benefits of SGLT2i on LV and RV function. Natriuretic peptides are strongly related to LV remodeling and hemodynamic and neurohormonal status . For thiOur study had other several limitations. We enrolled a small group of patients. Although we attempted to minimize the limitations related to an observational study by evaluating patients with a long history of CHF under optimal medical therapy and by serially analyzing changes in systolic parameters in comparison with baseline and previous echocardiographic evaluations, the absence of a control group without SGLT2i represents a significant limitation. A control group would have allowed for a more robust comparison and assessment of the specific effects of SGLT2i treatment. Additionally, it is worth noting that only a small number of patients in our series was affected by diabetes. This disparity is because, in Italy, diabetic patients might have already received therapy with SGLT2i, while this option was available only to non-diabetic patients since the beginning of our enrollment. Therefore, the influence of baseline metabolic status on the response in terms of systolic function should be further investigated in future studies. By acknowledging these limitations, we can better contextualize the results of this study, and future research can build upon these findings to address these gaps in understanding.For patients with HFrEF undergoing optimal medical therapy, the administration of SGLT2i was associated with a short to midterm improvement in both LV and RV function. These data provide new evidence about the mechanisms underlying the beneficial effects of this class of drugs, suggesting the direct and indirect effects of SGLT2i. Further studies should confirm these data and better clarify the relationship between RV and LV improvement and the influence of diabetes.