Monaldi Hospital

Background Some implantable cardioverter defibrillators (ICD) are equipped with diagnostic algorithms that combine data from multiple sensors. The HeartLogic Index was shown to accurately stratify patients at risk of heart failure (HF) events. However, there are no data on its performance in the presence of atrial fibrillation (AF). We evaluated and compared the performance of the algorithm during sinus rhythm and during long-lasting AF episodes. Methods The feature was activated in 568 ICD patients from 26 centers. We analyzed stored data to identify periods of ≥30 consecutive days with atrial high-rate episode (AHRE) burden <1hour/day, and periods with AHRE burden ≥20hours/day. Then, we identified patients who met both conditions during their follow-up (AHRE group, N=53), to allow pairwise comparison of periods. For control purposes, we identified patients with AHRE burden <1h during the entire follow-up and we implemented a 2:1 propensity score matching versus the AHRE group (Matched non-AHRE group, N=106). Results In the AHRE group, the rate of HeartLogic alerts was 1.2 (95%CI:1.0-1.5) /patient-year during periods with AHRE burden <1hour/day and 2.0 (95%CI:1.5-2.6) /patient-year during AHRE burden ≥20hours/day periods (p=0.004). Significantly higher values of the combined index were recorded during periods with AHRE burden ≥20 hours/day (in Figure the average combined index – Day 0: alert day). The rate of HF hospitalizations was 0.34 (95%CI:0.15-0.69) /patient-year during IN-alert periods and 0.06 (95%CI:0.02-0.14) /patient-year during OUT-of-alert periods (p<0.001). The IN/OUT-of-alert state incidence rate ratio of HF hospitalizations was 8.59 (95%CI:1.67-55.31) during periods with AHRE burden <1hour/day and 2.70 (95%CI:1.01-28.33) during AHRE burden ≥20hours/day periods. In the Matched non-AHRE group, the rate of HF hospitalizations was 0.29 (95%CI:0.12-0.60) /patient-year during IN-alert periods, and 0.04 (95%CI:0.02-0.08) /patient-year during OUT-of-alert periods (p<0.001). The incidence rate ratio was 7.11 (95% CI: 2.19-22.44). Conclusions Patients seemed more exposed to alerts during periods of AF. The ability of the algorithm to identify increased risk of HF events was confirmed during AF, despite a lower IN/OUT-of-alert incidence rate ratio when compared to non-AF periods and non-AF patients.

Background Real world data indicate that PCSK9 inhibitors (PCSK9i) are started in very high-risk patients at higher LDL cholesterol (LDL-C) values than those recommended by guidelines. Different reimbursement rules may have an impact on access to injectable therapy among different countries. In Italy, reimbursement of injectable lipid lowering therapies (LLT) (i.e., PCSK9i and inclisiran) has been recently allowed for very high risk patients with LDL-C levels >70 mg/dl while on statin/ezetimibe LLT or statin intolerant, and, thereafter, inclisiran has been introduced in clinical practice. No data are available on inclisiran real world use in Italy and on the impact of new reimbursement rules on patient access to inclisiran. Purpose Cholinet (Cholesterol inclisiran Italian network) is an Italian multicenter prospective phase 4 registry involving 21 Italian centers, designed to assess efficacy, safety, adherence and persistence, as well characteristics of very high risk patients with atherosclerotic CV disease (ASCVD) and/or familial hypercholesterolemia (FH) receiving inclisiran. Methods From November 2022 through February 2023, the Cholinet registry enrolled patients receiving inclisiran due to elevated LDL-C levels in Italian centers as part of their medical therapy. Baseline characteristics, concomitant therapies, blood chemistry, were recorded at the time of first prescription and at follow-up. Results We enrolled 105 patients (14% FH, 30% female, mean age 64 years) receiving inclisiran according to standard clinical practice. 37 of them reached 3 months follow up (i.e., time of first reinjection dose) and none of them missed the reinjection dose. At the time of inclisiran first prescription median LDL-C was 96.6 mg/dl and reached 48.8 mg/dl at the time of 3 months observation (49% reduction). In patients with ASCVD median LDL-C at baseline was 90.4 mg/dL and 44.4 mg/dl at follow-up (51% reduction). In patients with FH median LDL-C at baseline was 177.4 mg/dL and 109.5 mg/dL at follow-up (38% reduction). Of 105 patients enrolled, 92 patients (88%) were on LLT. Heterogeneity was found on the LDL-C reduction across our cohort (Figure 1) (Shapiro-Wilk test p<0.05) that appeared to be influenced by background LLT (Kruskal-Wallis rank for previous PCSK9i exposure p=0.0028, for background LLT p=0.0435) (Figure 2), but not by baseline LDL-C levels (ANOVA p=0.06). LDL-C target was achieved in 21 (66%) of 32 patients receiving background LLT and in 2 (40%) of 5 patients who did not. No patient reported side effects. Conclusion These preliminary results from the Cholinet registry show that, in a context of facilitated reimbursement access, inclisiran is introduced at substantially lower baseline LDL-C values than previously reported for PCSK9i, reflecting a favorable change in clinical practice. Inclisiran effectively and safely reduces LDL-C in patients with ASCVD or FH, with some etherogeneity that was associated with background LLT.Kernel density plot, LDL-C % reductionStratified Kernel density plot

Background Heart failure (HF) with preserved ejection fraction (HFpEF) represents about 50% of new HF diagnosis but still lacks specific biomarkers and effective therapy. Epigenetic-sensitive changes accumulated over time, mainly guided by DNA methylation and demethylation, can lead to chromatin remodelling and affect transcriptional molecular networks underlying microvascular inflammation, oxidative stress, and maladaptive cardiac remodelling which predispose synergistically to HFpEF. Purpose We hypothesize that circulating genome-wide DNA methylation profiles may identify novel biomarkers for discriminating HFpEF vs. HF with reduced EF (HFrEF) and provide insight into the underlying pathophysiology of disease. Methods A total of n=47 subjects were enrolled including patients with HFpEF (n=22) and HFrEF (n=13) as well as healthy subjects (n=12) serving as control group (CON). Starting from pheripheral blood biospecimens, we isolated CD4+ T cells and extracted genomic DNA for genome-wide methylome analysis and total RNA for experimental validation set. Results The reduced representation bisulfite sequencing (RRBS) revealed that patients with HFpEF had unique variations in DNA methylation profiles as compared to HFrEF and CON groups and reflected distinct pathogenic mechanisms. Using the list of differentially methylated CpG sites in HFpEF, we performed a complex network analysis to indentify the "HFpEF interactome" (Fig.1 A-B). Then, using the DisGeNET database we extracted n=12 candidate genes which were already associated with diastolic dysfunction, cardiac hypertrophy, cardiac fibrosis, inflammation, obesity, and hypertension, as key pathophenotypes of HFpEF (Fig.1 C). The hub genes included the ACTB, VAV2, JUNB, HOOK2, SETD7, PNKP, ASAP1, PAICS, DNM1L, HIF1AN, MEF2D, and NRG1. Validation experiment set by qRT-PCR revealed that elevated mRNA levels of the JUNB, SETD7, and MEF2D hypermethylated genes significantly discriminated HFpEF patients vs. CON (p<0.01, p<0.01, p<0.001, respectively) and vs. HFrEF patients (p<0.05, p<0.01, p<0.001, respectively) (Fig. 2A). Receiver operating characteristic (ROC) curve showed that network-oriented JUNB (AUC: 1, p<0.001), SETD7 (AUC: 0.97, p<0.01), and MEF2D (AUC: 1, p<0.001) genes have a high diagnostic accuracy in discriminating HFpEF vs. CON as well as HFpEF vs. HFrEF (AUC: 1, p<0.01, AUC: 0.97, p<0.01, AUC: 1, p<0.001, respectively) (Fig. 2B). Conclusions Circulating CD4+ T cell-derived hypermethylation of JUNB, SETD7, and MEF2D may reveal novel molecular drivers of HFpEF and suggest possible biomarkers to optimize patient phenotyping.

Background Sodium-glucose Cotransporter-2(SGLT2) inhibitors are currently recommended as first line therapy for all patients with heart failure with reduced ejection fraction (HFrEF).Adults with a systemic right ventricle (sRV) may develop progressive systolic dysfunction during follow-up. Optimal medical therapy for HFrEF remains still to be determined in this complex population. Purpose We aimed to assess safety and evaluate potential clinical benefit of dapagliflozin in patients with a sRV compared to standard medical treatment for HF. Methods Inclusion criteria were:age ≥ 18 years; transposition of the great arteries (TGA) following Senning/Mustard repair or congenitally corrected TGA, sRV EF ≤ 40%, already on optimized medical therapy including sacubitril/valsartan for at least 3 months. Exclusion criteria were: systolic blood pressure (SBP) <90 mmHg, glomerular filtration rate (GFR)<30ml/min and univentricular physiology. All eligible patients attending our tertiary center for adult congenital heart disease were randomly assigned to the treatment or control group. Patients in the treatment arm were prescribed 10 mg dapagliflozin o.d. on top of their medical therapy, while control group continued standard therapy. Patients were scheduled for a structured follow-up including clinical evaluation, blood test, echocardiography, and 6 minute-walking at 6 months from study inclusion for both groups. Results Fifty patients (41±11 years, 54% male, 64% TGA) met the inclusion criteria: 25(50%) were started on 10 mg dapagliflozin. There was no significant difference in terms of age (p=0.4), sex(p=0.1), anatomy(p=0.2) and baseline sRV EF (p=0.2). Up to February 2023, 14 patients in the treatment group and 13 controls completed the 6-month follow-up. Clinical and echocardiographic findings at baseline and at 6-month in the treatment group are summarized in Table1: dapagliflozin was well tolerated and no major adverse events were reported. Treatment did not impact on the systolic blood pressure and renal function. However a significant improvement in the sRV freewall global longitudinal strain(GLS) was found (-15.8±3 Vs -18.3±3; p=0.03). Differences in main echocardiographic indices of sRV systolic function between baseline and follow-up in the two arms are shown in Table2: treatment resulted in significant positive changes of sRV FAC, GLS, and free wall GLS compared to the group on standard therapy. Conclusions Initial results from the ongoing single-centre DAPA-SERVE trial provided reassuring data on the safety profile of dapagliflozin in patients with a sRV. Furthermore, significant improvement of echocardiographic indices of sRV function in patients on dapagliflozin compared to those on standard medical therapy was demonstrated at 6-month. Longer follow-up is warranted to determine the clinical impact of those positive changes and to shed light on the potential benefit of SGLT2 inhibitors use on top of standard therapy in this complex population.

Background Patients with repaired Tetralogy of Fallot (rToF) present anatomic and hemodynamic sequelae which may impact the right heart mechanics. Right ventricular adaptation to prolonged loading conditions should not be considered in isolation from the right atrium, because the atrial function affects that of the ventricle. Purpose This study aims to describe the right atrial performance using the echocardiographic right atrial longitudinal strain in a population of adult patients with rToF. Methods Echocardiographic images of adult patients (>18 years old) with rToF were retrospectively reviewed, and atrial reservoir (rRAS), conduit (cRAS), and contractile (aRAS) right atrial longitudinal strain were calculated. A group of healthy subjects (CTR) with comparable sex, age, and body surface area was included for comparison. Invasive cardiac catheterization data were also collected for patients with rToF. Results Sixty patients were included in the study: 30 with rToF (age 34 ± 9 years old) and 30 healthy subjects (age 34 ± 11 years old). Patients with rToF presented a lower value of rRAS, cRAS, and aRAS when compared to CTR (rRAS: rToF 20.83 ± 8.44% vs CTR 36.22 ± 9.53%, p<0.0001; cRAS: rToF -11.22 ± 6.41% vs CTR -22.67% ± 8.88%, p<0.0001; aRAS: rToF 9.67 ± 5.94% vs CTR 14.28 ± 6.35%, p=0.03). rRAS presented a good positive correlation with systolic peak velocity at tissue doppler imaging (p=0.006) and a trend toward positive correlation with right ventricle global longitudinal strain (p=0.08) and with the tricuspid annular plane systolic excursion (p=0.07). No correlation was found between invasive right ventricle end-diastolic and -systolic pressure and echocardiographic right atrial longitudinal strain parameters. Conclusion Adult patients with rToF presented a lower value of right atrial longitudinal strain, indicating an impaired atrial performance. Right atrial longitudinal strain provides additional insight for the comprehensive evaluation of right heart mechanics and should be systematically evaluated during the follow-up of adult patients with rToF.

Background Pulmonary arterial hypertension (PAH)-targeted therapies exert significant hemodynamic changes. We aimed to systematically synthesize these effects and explore the pulmonary pressure and flow changes in relation to the resistance changes. Methods We systematically searched PubMed, CENTRAL, and Web of Science for studies evaluating the hemodynamic effects (mean pulmonary artery pressure [mPAP], cardiac index/output [CI/CO], pulmonary vascular resistance [PVR]) of PAH-targeted therapies (comprising endothelin receptor antagonists [ERA], phosphodiesterase type 5 inhibitors [PDE5i], prostanoids [either i.v./s.c. or p.o./inh], riociguat, and selexipag) either in monotherapy or combinations as assessed by right heart catheterization (RHC) in treatment-naïve PAH patients. We performed a random-effects meta-analysis and used meta-regression to evaluate the contribution of mPAP % reduction and CI/CO % increase on the PVR % reduction across different treatment groups. Results We included 68 studies comprising 90 treatment groups and 4276 patients (age 47.3±13.2, 74% women). PVR reduction as a percentage of the pre-treatment value was more pronounced in the oral + prostanoid i.v./s.c. combination therapy (mean difference [MD] -50.0%, 95% confidence interval [CI] -60.8%; -39.2%), compared to oral combination therapy (MD -41.7%, 95% CI -47.6%; -35.8%), prostanoid i.v./s.c. monotherapy (MD -31.8%, 95% CI -37.6%; -25.9%), and oral monotherapy (MD -21.6%, 95% CI -25.4%; -17.8%) (Figure 1). The contribution of mPAP % reduction and of CI/CO % increase to the PVR % reduction was equally significant in all treatment groups (Figure 2). In the oral combination therapy group CI/CO % increase had superior contribution over mPAP % reduction (R2 90% vs R2 0%), but this difference was driven by an outlier study with n = 8 patients and after the exclusion of the outlier, the contribution of mPAP % reduction and of CI/CO % increase to the PVR % reduction was equally significant also in the oral combination group. The same results applied in a sensitivity analysis including only studies with idiopathic/heritable/drugs-induced/connective tissue disease-associated PAH patients. Conclusion Combination therapies, especially with the inclusion of parenteral prostanoids, lead to remarkable hemodynamic improvement in treatment-naïve PAH patients. The contribution of mPAP and CI/CO % changes to the overall PVR % reduction is equally significant.Figure 1Figure 2

At the beginning of the COVID-19 emergency, non-urgent surgical procedures had to be deferred, but also emergencies were reduced. To assess the global trend of pacemaker (PM) and implantable cardiac-defibrillator (ICD) procedures performed in Italy before, during, and after the first COVID-19 emergency, all the Italian hospital discharge records related to PM/ICD procedures performed between 2012 and 2021, sent to the National Institute of Health, were reviewed. Compared to 2019, in 2020, there was a reduction of first PM implants (52,216 to 43,962, −16%; p < 0.01), but not replacements (16,591 to 17,331, + 4%; p = 0.16). In particular, in April 2020, there was a drop of first implants (− 53,4% vs the average value of April 2018 and April 2019; p < 0.01), while the reduction of replacements was less evident (−32.6%; p = NS). In 2021, PM procedures increased to values similar to the pre-pandemic period. A reduction of ICD procedures was observed in 2020 (22,355, −7% toward 2019), mainly in April 2020 (− 46% vs April 2018/April 2019; p = 0.03). In 2021, the rate of ICD procedures increased (+ 14% toward 2020). A non-significant reduction of “urgent” procedures (complete atrioventricular block for PM and ventricular fibrillation for ICD), even in April 2020, was observed. In 2020, there was a reduction of first PM implants and ICDs, offset by increased activity in 2021. No decrease in PM replacements was observed, and the drop in “urgent” PM and ICD procedures was not statistically significant.

Background Alpha-1 antitrypsin, also known as alpha1 proteinase inhibitor, is a protein 90% synthesized by hepatocytes. Alpha-1 antitrypsin deficiency should be suspected if patients have unexplained emphysema or liver disease in the absence of others recognized causes. The diagnosis is based on tests that measure the amount of the enzyme in the blood and confirm by molecular analysis. Case presentation We present the case of a man of Caucasian ethnicity, who started experiencing difficulty in breathing 20 years after liver transplantation. After about 30 years since transplantation, an intermediate alpha-1 antitrypsin deficiency is diagnosed with evidence of air trapping, pulmonary emphysema and bronchiectasis. Conclusion The presence of a Z-variant synthesized from the donor liver may have contribute to the onset of respiratory disease.

Tetralogy of Fallot (TOF) is the most common complex congenital heart disease with long-term survivors, demanding serial monitoring of the possible complications that can be encountered from the diagnosis to long-term follow-up. Cardiovascular imaging is key in the diagnosis and serial assessment of TOF patients, guiding patients’ management and providing prognostic information. Thorough knowledge of the pathophysiology and expected sequalae in TOF, as well as the advantages and limitations of different non-invasive imaging modalities that can be used for diagnosis and follow-up, is the key to ensuring optimal management of patients with TOF. The aim of this manuscript is to provide a comprehensive overview of the role of each modality and common protocols used in clinical practice in the assessment of TOF patients.

Hepatocellular carcinoma (HCC) is a predominant malignancy with increasing incidences and mortalities worldwide. In Western countries, the progressive affirmation of Non-alcoholic Fatty Liver Disease (NAFLD) as the main chronic liver disorder in which HCC occurrence is appreciable even in non-cirrhotic stages, constitutes a real health emergency. In light of this, a further comprehension of molecular pathways supporting HCC onset and progression represents a current research challenge to achieve more tailored prognostic models and appropriate therapeutic approaches. RNA non-coding transcripts (ncRNAs) are involved in the regulation of several cancer-related processes, including HCC. When dysregulated, these molecules, conventionally classified as “small ncRNAs” (sncRNAs) and “long ncRNAs” (lncRNAs) have been reported to markedly influence HCC-related progression mechanisms. In this review, we describe the main dysregulated ncRNAs and the relative molecular pathways involved in HCC progression, analyzing their implications in certain etiologically related contexts, and their applicability in clinical practice as novel diagnostic, prognostic, and therapeutic tools. Finally, given the growing evidence supporting the immune system response, the oxidative stress-regulated mechanisms, and the gut microbiota composition as relevant emerging elements mutually influencing liver-cancerogenesis processes, we investigate the relationship of ncRNAs with this triad, shedding light on novel pathogenetic frontiers of HCC progression.

Subcutaneous implantable cardioverter defibrillators (S-ICD) are widely accepted therapy in congenital heart disease (CHD) patients at risk of life-threatening ventricular arrhythmias or sudden cardiac death (SCD) when pacing is not required. Occasionally, pacemaker (PM)-dependent CHD patients will subsequently develop an indication for a cardioverter defibrillator. The use of S-ICD in complex CHD patients who have had already PM devices implanted implies some specific considerations, as the safety for these patients in unknown and recommendations among physicians may vary widely. We review the data and studied the indications for S-ICD in complex CHD with previous PM and discuss its usefulness in clinical practice. From a large cohort of 345 patients enrolled in the S-ICD Monaldi care registry, which encompass all the patients implanted in the Monaldi Hospital of Naples, we considered 11 consecutive complex CHD patients (10M/1F aged 40.4 ±18.4 years) who underwent S-ICD implant after a previous PM implant, from February 2015 to October 2022. Mean follow-up was 25.5 ± 22 months. All the patients showed a good compliance to the device system with no complications (infections or skin erosions). In complex CHD with already implanted PM devices, S-ICD implant appears to be a safe alternative to PM upgrading to transvenous ICD system, avoiding abandoned leads or life-threatening lead extraction. However, there are important issues with regard to testing and programming that need to be addressed at the time of implantation.

Leiomyoma is the most common benign tumor of the esophagus. Open thoracotomy, the traditional approach adopted for the enucleation of the esophageal leiomyoma, over the years, has been gradually replaced by video-assisted thoracoscopic surgery. However, this minimally invasive approach has limitations, such as two-dimensional vision and reduced range of motion, which have recently been overcome by technical advantages of robot-assisted surgery. In the surgical management of circumferential esophageal leiomyoma, a combined use of robotic surgery and intraoperative endoscopy may be helpful to facilitate tumor enucleation and to prevent esophageal mucosal injury during the surgical procedure.

Traditionally, to make the patient “free” from the ventilator, the work of breathing is transferred from the machine to the human as soon as possible. To minimize reliance on external support, clinicians continually balance the need to extubate their patients promptly with the risk of extubation failure and the resulting impact on outcomes. In fact, we know that in the event of extubation failure, there is a strong association with the risk of prolonged mechanical ventilation, prolonged ICU stay, high mortality, and increased cost of care. Many authors have applied non-invasive support to their weaning strategies, but patients must be carefully selected because the indiscriminate use of NIV does not lead to particular advantages in all patients. Indeed, according to the currently available evidence, NIV should be used to prevent post-extubation respiratory failure in high-risk patients, while its use is not recommended in non-high-risk patients. Patients with COPD appear to benefit from this type of weaning. Additionally, there does not appear to be any benefit of using NIV for the treatment of post-extubation respiratory failure according to the RCT, although careful monitoring of patients with NIV and timely reintubation probably can avoid potential harm. Another temptation offered by NIV is to remove the endotracheal tube as soon as possible to decrease the duration of mechanical ventilation. A probably effective alternative has recently been proposed with the use of high flow nasal oxygen, but not as effective as the preventative use of NIV. To date, although with conflicting data indicating that NIV is irrelevant for most patients if applied as therapy and not as post-extubation prophylaxis, we know that it reduces post-extubation respiratory distress, avoids reintubation, and improves survival.

During non-invasive mechanical ventilation (NIV) for respiratory failure, patient comfort cannot be less important than treatment effectiveness. Humidification increases the chances of success in applying NIV as it is related to managing respiratory secretions and increasing the feeling of well-being. Interface selection is a significant determinant of NIV success or failure, and the number and types of NIV interfaces have increased. New varieties are being developed, but we know how humidification prevents cold gas and dry effects. The heated humidifier provides better CO2 elimination and less breathing work than the heat and humidity exchanger because the heated humidifier adds less dead space. There is the possibility of using the respiratory system as an alternative route for administering drugs for many drug therapies. The administration of aerosol medications can provide many advantages over conventional treatment. Since respiratory diseases are the most common causes of serious illness, the use of aerosol therapy to deliver high concentrations of local drugs with minimal systemic side effects makes this an attractive option. To date, limited evidence has limited its more comprehensive application. We recognize that the effectiveness of aerosol drug therapy depends on drug-related factors (particle size, molecular weight), device-related factors, patient-related factors (airway anatomy, inhalation patterns), and mechanical ventilation-related factors (humidification, airways).

Cardiothoracic and thoracic surgery postoperative pulmonary complications (PPCs) are common. With atelectasis as the underlying event of PPCs, it is not surprising that NIV is seen as a useful resource in the management of such patients. In cardiothoracic surgery, prophylactic NIV should be used for patients presenting risk factors for postoperative hypoxemia aiming to prevent PPCs. Early studies of preventive NIV in cardiothoracic surgery showed steady improvement in oxygenation, but mixed results in terms of reduction of atelectasis. Lately, the use of high-flow oxygen therapy has spread to ICUs, proving to guarantee good results when used as prophylaxis in patients with low and high risk of re-intubation, but there is no difference in the incidence of PPCs or mortality. In thoracic surgery, the pathophysiological timing of atelectasis development is common to that of cardiac surgery. The main difference lies in the typical characteristics of the lung cancer patients who commonly suffer from COPD, so the possibility of weaning may be more difficult. On the other hand, recent lung resection, if subjected to NIV, may result in the development or worsening of air leakage, and therefore this factor must be added to the decision-making balance. The Italian intersociety consensus on Perioperative Anaesthesia Care in Thoracic surgery (2020) recommends the use of NIV or CPAP to treat acute respiratory failure complicating thoracic surgery; furthermore, the use of high-flow oxygen therapy as an alternative or integrative support to CPAP or NIV is still viable to treat acute respiratory failure in thoracic surgery.

Background In patients with heart failure with reduced ejection fraction (HFrEF), treatment with sacubitril–valsartan (S/V) may reverse left ventricular remodeling (rLVR). Whether this effect is superior to that induced by other renin–angiotensin system (RAS) inhibitors is not well known. Methods HFrEF patients treated with S/V (n = 795) were compared, by propensity score matching, with a historical cohort of 831 HFrEF patients (non-S/V group) treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (RAS inhibitors). All patients were also treated with beta-blockers and shared the same protocol with repeat echocardiogram 8–12 months after starting therapy. The difference-in-difference (DiD) analysis was used to evaluate the impact of S/V on CR indices between the two groups. Results After propensity score matching, compared to non-S/V group (n = 354), S/V group (n = 354) showed a relative greater reduction in end-diastolic and end-systolic volume index (ESVI), and greater increase in ejection fraction (DiD estimator = + 5.42 mL/m², P = 0.0005; + 4.68 mL/m², P = 0.0009, and + 1.76%, P = 0.002, respectively). Reverse LVR (reduction in ESVI ≥ 15% from baseline) was more prevalent in S/V than in non-S/V group (34% vs 26%, P = 0.017), while adverse LVR (aLVR, increase in ESVI at follow-up ≥ 15%) was more frequent in non-S/V than in S/V (16% vs 7%, P < 0.001). The beneficial effect of S/V on CR over other RAS inhibitors was appreciable across a wide range of patient’s age and baseline end-diastolic volume index, but it tended to attenuate in more dilated left ventricles (P for interaction = NS for both). Conclusion In HFrEF patients treated with beta-blockers, sacubitril/valsartan is associated with a relative greater benefit in LV reverse remodeling indices than other RAS inhibitors. Graphical abstract