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Background: Raphe-type bicuspid aortic valve (BAV) is a potential hostile scenario in trans-catheter aortic valve replacement (TAVR) due to pronounced calcium burden, possibly associated with tapered valve configuration. Trans-Catheter heart valve (THV) sizing strategy (annular vs. supra-annular) is controversial in this valve subtype., Objectives: To describe the phenotypical characteristics of severe, tapered, raphe-type, BAV stenosis undergoing TAVR and to explore safety and efficacy of modern-generation THVs, analysing the impact of annular and supra-annular sizing strategies on short- and mid-terms outcomes., Methods: This is a retrospective, multicenter registry enrolling consecutive stenotic Sievers type 1 BAV treated with TAVR. Study population was divided into tapered and non-tapered configuration according to MSCT analysis. Matched comparison between annular and supra-annular sizing groups was performed in tapered population., Results: From January 2016 to June 2023, 897 patients were enrolled. Of them, 696 patients displayed a tapered configuration. Of those, 510 received a THV according to annular sizing. After propensity score matching 186 matched pairs were selected. Technical success (96.2 % vs 94.1 %, OR 1.61 [0.61-4.24], p = 0.34), 30-day device success (83.6 % in both groups, OR 1.42 [0.78-2.57], p = 0.25) and 30-day early safety (71.8 % vs 70.5 %, OR 1.07 [0.68-1.68], p = 0.78) were similar between the annular and supra-annular sizing groups; a higher post-TAVR gradient was observed in supra-annular group, although it was only 2 mmHg mean. At mid-term follow-up, the rate of clinical efficacy was 84.7 %., Conclusions: TAVR with modern-generation devices is safe and effective for tapered raphe-type BAV, showing comparable results for annular and supra-annular sizing strategies., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Patients experiencing non-ST segment elevation acute-coronary-syndromes (NSTE-ACS) often present with multivessel-coronary-artery-disease (MVD). An immediate complete multivessel revascularization (MVR) - within the index hospitalization - may be considered the default therapeutic strategy, although its risk-to-benefit profile has not been definitively established through dedicated clinical trials., Methods: A systematic review and meta-analysis, adhering to MOOSE and PRISMA guidelines, was conducted to assess studies comparing immediate MVR versus a conservative culprit-only revascularization (COR) in NSTE-ACS with MVD. The main endpoints were all-cause death, major adverse cardiovascular events (MACE) and non-fatal myocardial infarction (MI). The incidence of any revascularization or further percutaneous-coronary-interventions (PCIs) were also collected. The primary analyses for the main endpoints were conducted on propensity-matched groups only., Results: A total of 22 studies (182,798 patients) were identified. 7 studies, encompassing 11,372 patients, were included in the primary analysis of propensity score-matched groups. Immediate MVR significantly increased (28%) survival (OR 0.72, 95% CI 0.58-0.90, P < 0.01) along with a 35% reduction in MACE (OR 0.65, 95% CI 0.47-0.88, P = 0.01) and a 60% decrease in MI (OR 0.40, 95% CI 0.25-0.63, P < 0.01) during a mean 3-years follow-up compared to the propensity score-matched COR group. Results were consistent in the unmatched analyses., Conclusions: This meta-analysis supports an immediate MVR for improving clinical outcomes in patients with NSTE-ACS and MVD as compared to a conservative immediate COR. These data prompt further evaluations regarding optimal strategies in the pursuit of MVR, including patient selection, revascularization modality, and assessment methods of revascularization completeness., Competing Interests: Declaration of competing interest Francesco Bianchini received a research grant from Abbott Vascular. Enrico Romagnoli received speaker fees from Abbott, Abiomed and Terumo.Cristina Aurigemma has been involved in advisory board activities by Abbott, Abiomed, Medtronic, and Biotronic. Lazzaro Paraggio received speaker fees from Abiomed and Terumo. Mattia Lunardi received speaker fees from Medtronic. Antonio Maria Leone received speakers' fees from Abbott Vascular, Medtronic, Menarini, Bayer, Daichii Sankyo, Bruno. Giuseppe Biondi-Zoccai has consulted for Amarin, Balmed, Cardionovum, Crannmedical, Endocore Lab, Eukon, Guidotti, Innovheart, Meditrial, Microport, Opsens Medical, Terumo, and Translumina, outside the present work. Carlo Trani and Francesco Burzotta received speaker fees from Abbott Vascular, Abiomed, Medtronic and Terumo. The other authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Background: Trans-femoral (TF) represents the main access for TAVI. Although there are various technical strategies to conduct TF-TAVI (pacing modality, secondary arterial access, primary access puncture etc.), the optimal technique is not recognized., Aims: In the present study, we assessed the impact of systematic use of LITE-TAVI in terms of feasibility, safety, and main access complication management using VARC-3 outcomes definitions., Methods: At our institution, a less-invasive totally-endovascular (LITE) technique for TF-TAVI has been developed since 2017. Key aspects are: precise TAVI access puncture using angiographic-guidewire ultrasound guidance; radial/ulnar approach as the default "secondary access"; non-invasive pacing (by guidewire stimulation or definitive pacemaker external programmer)., Results: 1022 consecutive TF-TAVI patients (55 % women, mean age: 80 years, mean EuroSCORE II 6.1 %, mean STS-PROM 4.3 %, mean STS/ACC TVT TAVR mortality score 3.4 %) were approached using the LITE technique. Technical success was achieved in 993 (97.2 %) patients. Access-related major vascular complications occurred in 12 (1.2 %) and VARC-3 ≥ type 2 bleedings in 12 (1.2 %) patients. At 30-day, all-cause death occurred in 17 (1.7 %) patients. This figure resulted significantly lower than expected on the bases of the mortality predicted not only by EuroSCORE II (6.1 %, p < 0.001) and STS-PROM score (4.3 %; p < 0.001), but also by STS/ACC TVT TAVR mortality score (3.4 %; p = 0.01)., Conclusions: Systematic use of LITE-TAVI is feasible and is associated with an extremely low rate of access-related bleeding and vascular complications which may drive to outcome improvement., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Background: Balloon-expandable valves (BEVs) and self-expanding valves (SEVs) have different features that may impact the outcomes of patients with Sievers type 1 bicuspid aortic valve (BAV) stenosis undergoing transcatheter aortic valve replacement., Objectives: This study sought to compare procedural and clinical outcomes of BEVs and SEVs in Sievers type 1 BAV stenosis., Methods: AD-HOC (Characteristics, Sizing, and Outcomes of Stenotic Raphe-Type Bicuspid Aortic Valves Treated With Transcatheter Device Implantation) is an observational registry enrolling patients with Sievers type 1 BAV stenosis undergoing transcatheter aortic valve replacement with current-generation BEVs and SEVs at 24 international centers. A 1:1 propensity score matching analysis was performed to adjust for baseline imbalances. The primary endpoint was midterm major adverse events, defined as a composite of all-cause death, neurologic events, or hospitalization for heart failure., Results: Among 955 eligible patients, propensity score matching resulted in 301 pairs. At a median follow-up of 1.3 years, BEVs and SEVs had a similar risk of major adverse events (BEV vs SEV: HR: 0.75; 95% CI: 0.49-1.16; P = 0.200). Technical success was similar (OR: 1.38; 95% CI: 0.63-3.04; P = 0.421). At 30 days, BEVs were associated with a lower risk of new permanent pacemaker implantation (OR: 0.42; 95% CI: 0.24-0.72; P = 0.002) and moderate or greater paravalvular regurgitation (OR: 0.16; 95% CI: 0.05-0.48; P = 0.001) but a higher risk of severe patient-prosthesis mismatch (OR: 3.03; 95% CI 1.02-8.95; P = 0.045)., Conclusions: Current-generation BEVs and SEVs proved similar technical success and midterm clinical efficacy in Sievers type 1 BAV stenosis. Compared to SEVs, BEVs were associated with less permanent pacemaker implantation and moderate or greater paravalvular regurgitation but with more severe patient-prosthesis mismatch., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Transfemoral access is nowadays required for an increasing number of percutaneous procedures, such as structural heart interventions, mechanical circulatory support, and interventional electrophysiology/pacing. Despite technological advancements and improved techniques, these devices necessitate large-bore (≥12 French) arterial/venous sheaths, posing a significant risk of bleeding and vascular complications, whose occurrence has been related to an increase in morbidity and mortality. Therefore, optimizing large-bore vascular access management is crucial in endovascular interventions. Technical options, including optimized preprocedural planning and proper selection and utilization of vascular closure devices, have been developed to increase safety. This review explores the comprehensive management of large-bore accesses, from optimal vascular puncture to sheath removal. It also discusses strategies for managing closure device failure, with the goal of minimizing vascular complications., Competing Interests: Drs Burzotta and Trani received speaker fees from Abbott Vascular, Abiomed, Medtronic, and Terumo. Dr Paraggio received speaker fees from Abiomed and Terumo. Dr Aurigemma received speaker fees from Abbott Vascular, Abiomed, Medtronic, Terumo, and Daiichi Sankyo. Dr Romagnoli received speaker fees from Abiomed, Abbott Vascular, and Terumo. Dr Bianchini received a research grant from Abbott Vascular. The other authors report no conflicts of interest to declare.

New-generation transcatheter heart valves have significantly improved technical success and procedural safety of transcatheter aortic valve implantation (TAVI) procedures; however, the incidence of permanent pacemaker implantation (PPI) remains a concern. This study aimed to assess the role of anatomic annulus features in determining periprocedural conduction disturbances leading to new PPI after TAVI using the last-generation Edwards SAPIEN balloon-expandable valves. In the context of a prospective single-center registry, we integrated the clinical and procedural predictors of PPI with anatomic data derived from multislice computed tomography. A total of 210 consecutive patients treated with balloon-expandable Edwards transcatheter heart valve were included in the study from 2015 to 2023. Technical success was achieved in 197 procedures (93.8%), and 26 patients (12.4%) required new PPI at the 30-day follow-up (median time to implantation 3 days). At the univariable logistic regression analysis, preprocedural right bundle branch block (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.01 to 4.97, p = 0.047), annulus eccentricity ≥0.25 (OR 5.43, 95% CI 2.21 to 13.36, p <0.001), calcium volume at annulus of the right coronary cusp >48 mm 3 (OR 2.60, 95% CI 1.13 to 5.96, p = 0.024), and prosthesis implantation depth greater than membranous septum length (OR 2.17, 95% CI 1.10 to 4.28, p = 0.026) were associated with new PPI risk. In the multivariable analysis, preprocedural right bundle branch block (OR 2.81, 95% CI 1.01 to 7.85, p = 0.049), annulus eccentricity ≥0.25 (OR 4.14, 95% CI 1.85 to 9.27, p <0.001), and annulus right coronary cusp calcium >48 mm 3 (OR 2.89, 95% CI 1.07 to 7.82, p = 0.037) were confirmed as independent predictors of new PPI. In conclusion, specific anatomic features of the aortic valve annulus might have an additive role in determining the occurrence of conduction disturbances in patients who underwent TAVI with balloon-expandable valves. This suggests the possibility to use multislice computed tomography to improve the prediction of post-TAVI new PPI risk., Competing Interests: Declaration of competing interest Dr. Romagnoli received speaker fees from Abbott Vascular and Terumo. F. Burzotta and C. Trani received speaker fees from Abbott Vascular, Abiomed, Medtronic, and Terumo. Dr. Aurigemma received speaker fees from Abbott Vascular, Abiomed, Medtronic, Terumo, and Daiichi Sankyo. Dr. Bianchini received a research grant from Abbott. The remaining authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve (BAV) stenosis is technically challenging and is burdened by an increased risk of paravalvular regurgitation (PVR)., Objectives: The aim of this study was to identify the incidence, predictors, and clinical outcomes of PVR after TAVR in Sievers type 1 BAV stenosis., Methods: Consecutive patients with Sievers type 1 BAV stenosis undergoing TAVR with current-generation transcatheter heart valves (THVs) in 24 international centers were enrolled. PVR was graded as none/trace, mild, moderate, and severe according to echocardiographic criteria. The endpoint of major adverse events (MAEs), defined as a composite of all-cause death, stroke, or hospitalization for heart failure, was assessed at the last available follow-up., Results: A total of 946 patients were enrolled. PVR occurred in 423 patients (44.7%)-mild, moderate, and severe in 387 (40.9%), 32 (3.4%), and 4 (0.4%) patients, respectively. Independent predictors of moderate or severe PVR were a larger virtual raphe ring perimeter (adjusted OR: 1.07; 95% CI: 1.02-1.13), severe annular or left ventricular outflow tract calcification (adjusted OR: 5.21; 95% CI: 1.45-18.77), a self-expanding valve (adjusted OR: 9.01; 95% CI: 2.09-38.86), and intentional supra-annular THV positioning (adjusted OR: 3.31; 95% CI: 1.04-10.54). At a median follow-up of 1.3 years (Q1-Q3: 0.5-2.4 years), moderate or severe PVR was associated with an increased risk of MAEs (adjusted HR: 2.52; 95% CI: 1.24-5.09)., Conclusions: After TAVR with current-generation THVs in Sievers type 1 BAV stenosis, moderate or severe PVR occurred in about 4% of cases and was associated with an increased risk of MAEs during follow-up., Competing Interests: Funding Support and Author Disclosures Dr Aurigemma has reported speaker fees from Abbott, Medtronic, Abiomed, and Terumo. Dr Trani has been involved in advisory board meetings or received speaker fees from Medtronic, Abbott, Terumo, Daiichi-Sankyo, and Abiomed. Dr Adamo has reported speaker honoraria from Abbott Vascular and Edwards Lifesciences. Dr Burzotta has been involved in advisory board meetings or has received speaker fees from Medtronic, Abbott, Terumo, Daiichi-Sankyo, and Abiomed. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Necrotizing enterocolitis (NEC) is a severe intestinal disease primarily affecting premature infants, marked by impaired epithelial regeneration. Breastfed infants are less susceptible to NEC than formula-fed ones, and human milk oligosaccharides (HMO) found in breast milk have prebiotic properties that can protect against NEC. However, it is unclear how HMOs influence intestinal epithelium regeneration in relation to the gut microbiota., Methods: Broad-spectrum antibiotics were administered to pregnant dams to reduce the microbiota in offspring. NEC was induced through administration of hyperosmolar formula, lipopolysaccharide, and hypoxia from postnatal days (p) 5-9. Intestinal epithelial organoids were derived from p9 mice. HMOs were isolated from human donor breast milk and then solubilized in the formula for each feed or culture media for organoids., Results: HMOs did not alter the microbiota profile in the presence of a normal or reduced microbiota. In the reduced microbiota, HMO treatment decreased NEC intestinal injury, and increased proliferation and stem cell activity. Additionally, in the complete absence of the microbiota, HMOs stimulated intestinal organoid growth., Conclusion: This study demonstrates that HMOs promoted intestinal epithelial regeneration independent of the gut microbiota. These findings provide further insight into the various benefits HMOs may have in the protection against NEC., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Several implant-based remote monitoring strategies are currently tested to optimize heart failure (HF) management by anticipating clinical decompensation and preventing hospitalization. Among these solutions, the modern implantable cardioverter-defibrillator and cardiac resynchronization therapy devices have been equipped with sensors allowing continuous monitoring of multiple preclinical markers of worsening HF, including factors of autonomic adaptation, patient activity, and intrathoracic impedance., Objectives: We aimed to assess whether implant-based multiparameter remote monitoring strategy for guided HF management improves clinical outcomes when compared to standard clinical care., Methods: A systematic literature research for randomized controlled trials (RCTs) comparing multiparameter-guided HF management versus standard of care was performed on PubMed, Embase, and CENTRAL databases. Incidence rate ratios (IRRs) and associated 95% confidence intervals (CIs) were calculated using the Poisson regression model with random study effects. The primary outcome was a composite of all-cause death and HF hospitalization events, whereas secondary endpoints included the individual components of the primary outcome., Results: Our meta-analysis included 6 RCTs, amounting to a total of 4869 patients with an average follow-up time of 18 months. Compared with standard clinical management, the multiparameter-guided strategy reduced the risk of the primary composite outcome (IRR 0.83, 95%CI 0.71-0.99), driven by statistically significant effect on both HF hospitalization events (IRR 0.75, 95%CI 0.61-0.93) and all-cause death (IRR 0.80, 95%CI 0.66-0.96)., Conclusion: Implant-based multiparameter remote monitoring strategy for guided HF management is associated with significant benefit on clinical outcomes compared to standard clinical care, providing a benefit on both hospitalization events and all-cause death., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background Guidelines recommend using multiple drugs in patients with heart failure (HF) with reduced ejection fraction, but there is a paucity of real-world data on the simultaneous initiation of the 4 pharmacological pillars at discharge after a decompensation event. Methods and Results A retrospective data mart, including patients diagnosed with HF, was implemented. Consecutively admitted patients with HF with reduced ejection fraction were selected through an automated approach and categorized according to the number/type of treatments prescribed at discharge. The prevalence of contraindications and cautions for HF with reduced ejection fraction treatments was systematically assessed. Logistic regression models were fitted to assess predictors of the number of treatments (≥2 versus <2 drugs) prescribed and the risk of rehospitalization. A population of 305 patients with a first episode of HF hospitalization and a diagnosis of HF with reduced ejection fraction (ejection fraction, <40%) was selected. At discharge, 49.2% received 2 current recommended drugs, β-blockers were prescribed in 93.4%, while a renin-angiotensin system inhibitor or an angiotensin receptor-neprilysin inhibitor was prescribed in 68.2%. A mineralocorticoid receptor antagonist was prescribed in 32.5%, although none of the patients showed contraindications to mineralocorticoid receptor antagonist prescription. A sodium-glucose cotransporter 2 inhibitor could be prescribed in 71.1% of patients. On the basis of current recommendations, 46.2% could receive the 4 foundational drugs at discharge. Renal dysfunction was associated with <2 foundational drugs prescribed. After adjusting for age and renal function, use of ≥2 drugs was associated with lower risk of rehospitalization during the 30 days after discharge. Conclusions A quadruple therapy could be directly implementable at discharge, potentially providing prognostic advantages. Renal dysfunction was the main prevalent condition limiting this approach.

Background and Aims: The use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) for the treatment of cardiogenic shock (CS) may result in left ventricle overload and distension. Percutaneous microaxial flow pump Impella in addition to VA-ECMO (ECPELLA) is an emerging option to overcome these collateral effects. Aim of this study is to assess whether the addition of Impella to VA-ECMO is an effective and safe unloading strategy., Methods and Results: We performed a systematic literature review of studies comparing ECPELLA vs. ECMO alone in patients with CS. The primary endpoint was early mortality (in-hospital or 30-day mortality). The secondary endpoints were bleeding, need for kidney replacement therapy, haemolysis, infections, and limb ischaemia. A total of 3469 potentially relevant articles were screened and eight retrospective studies including 11.137 patients were selected. There was no significant difference in early mortality (Risk Ratio, RR 0.90, 95% CI 0.78-1.03) between ECPELLA and ECMO. Nevertheless, there was a borderline significant reduction in early mortality with ECPELLA (RR 0.74, 95% CI 0.55-1.00) at sensitivity analysis selectively including studies reporting propensity matched analysis. ECPELLA was associated with increased bleeding (RR 1.45, 95% CI 1.20-1.75), need for kidney replacement therapy (RR 1.54, 95% CI 1.19-1.99), haemolysis (RR 1.71, 95% CI 1.41-2.07) and limb ischaemia (RR 1.43, 95% CI 1.17-1.75) and with a non-significant increase in severe infections (RR 1.26, 95% CI 0.84-1.89), compared with ECMO alone., Conclusion: Among patients with cardiogenic shock, ECPELLA is associated with increased complications compared with ECMO. Whether reducing ventricular overload with Impella among patients treated with ECMO reduces early mortality needs to be confirmed by further investigations., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: There is uncertainty about which diagnostic strategy for detecting coronary artery disease (CAD) provides better outcomes., Purpose: To compare the effect on clinical management and subsequent health effects of alternative diagnostic strategies for the initial assessment of suspected stable CAD., Data Sources: PubMed, Embase, and Cochrane Central Register of Controlled Trials., Study Selection: Randomized clinical trials comparing diagnostic strategies for CAD detection among patients with symptoms suggestive of stable CAD., Data Extraction: Three investigators independently extracted study data., Data Synthesis: The strongest available evidence was for 3 of the 6 comparisons: coronary computed tomography angiography (CCTA) versus invasive coronary angiography (ICA) (4 trials), CCTA versus exercise electrocardiography (ECG) (2 trials), and CCTA versus stress single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) (5 trials). Compared with direct ICA referral, CCTA was associated with no difference in cardiovascular death and myocardial infarction (relative risk [RR], 0.84 [95% CI, 0.52 to 1.35]; low certainty) but less index ICA (RR, 0.23 [CI, 0.22 to 0.25]; high certainty) and index revascularization (RR, 0.71 [CI, 0.63 to 0.80]; moderate certainty). Moreover, CCTA was associated with a reduction in cardiovascular death and myocardial infarction compared with exercise ECG (RR, 0.66 [CI, 0.44 to 0.99]; moderate certainty) and SPECT-MPI (RR, 0.64 [CI, 0.45 to 0.90]; high certainty). However, CCTA was associated with more index revascularization (RR, 1.78 [CI, 1.33 to 2.38]; moderate certainty) but less downstream testing (RR, 0.56 [CI, 0.45 to 0.71]; very low certainty) than exercise ECG. Low-certainty evidence compared SPECT-MPI versus exercise ECG (2 trials), SPECT-MPI versus stress cardiovascular magnetic resonance imaging (1 trial), and stress echocardiography versus exercise ECG (1 trial)., Limitation: Most comparisons primarily rely on a single study, many studies were underpowered to detect potential differences in direct health outcomes, and individual patient data were lacking., Conclusion: For the initial assessment of patients with suspected stable CAD, CCTA was associated with similar health effects to direct ICA referral, and with a health benefit compared with exercise ECG and SPECT-MPI. Further research is needed to better assess the relative performance of each diagnostic strategy., Primary Funding Source: None. (PROSPERO: CRD42022329635)., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-0231.

Aims: Adenosine has been tested in several randomized controlled trials (RCTs) to minimize the incidence of coronary microvascular obstruction (CMVO). The aim of this study was to pool all the RCTs comparing intracoronary or intravenous adenosine versus placebo in patients with acute coronary syndrome (ACS) undergoing myocardial revascularization., Methods and Results: PubMed and Scopus electronic databases were scanned for eligible studies up to 5th June 2022. A total of 26 RCTs with 5843 patients were included. Efficacy endpoints were major adverse cardiac events (MACE), all-cause death, non-fatal myocardial infarction, and heart failure. Atrioventricular blocks and ventricular fibrillation/sustained ventricular tachycardia (VF/SVT) were the safety endpoints. Myocardial blush grade, thrombolysis in myocardial infarction (TIMI) flow grade, left ventricular ejection fraction (LVEF), infarct size, and ST-segment resolution were also assessed. Adenosine administration was not associated with any clinical benefit in terms of MACE, all-cause death, non-fatal myocardial infarction, and heart failure. However, adenosine was associated with an increased rate of advanced atrioventricular blocks and of VF/SVT in studies with total mean ischaemic time >3 h, compared to placebo. Remarkably, among patients undergoing percutaneous coronary intervention, adenosine was associated with reduced myocardial blush grade 0-1 and TIMI flow grade 0-2, compared to placebo. Furthermore, adenosine did not show favourable effects on LVEF and infarct size., Conclusion: Adenosine infusion, as adjunctive therapy in ACS, was associated with an increased risk of advanced atrioventricular blocks and increased rates of adenosine-triggered ventricular arrhythmias in patients with long ischaemic time, without providing any clinical benefit compared to placebo., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The impact of myocardial revascularization on outcomes and prognosis in patients with chronic coronary syndrome (CCS) without left main (LM) disease or reduced left ventricle ejection fraction (LVEF) may be influenced by the revascularization strategy adopted., Methods: We performed a network meta-analysis including 18 randomized controlled trials comparing different revascularization strategies, including angiography-guided percutaneous coronary intervention (PCI), physiology-guided PCI and coronary artery bypass graft (CABG), in patients with CCS without LM disease or reduced LVEF., Results: Compared with medical therapy, all revascularization strategies were associated with a reduction of the primary endpoint, as defined in each trial, the extent of which was modest with angiography-guided PCI (IRR 0.86, 95% CI 0.75-0.99) and greater with physiology-guided PCI (IRR 0.60, 95% CI 0.47-0.77) and CABG (IRR 0.58, 95% CI 0.48-0.70). Moreover, angiography-guided PCI was associated with an increase of the primary endpoint compared to physiology-guided PCI (IRR 1.43, 95% CI 1.14-1.79) and CABG (IRR 1.49, 95% CI 1.27-1.74). CABG was the only strategy associated with reduced myocardial infarction (IRR 0.68, 95% CI 0.52-0.90), cardiovascular death (IRR 0.76, 95% CI 0.64-0.89), and all-cause death (IRR 0.87, 95% CI 0.77-0.99), but increased stroke (IRR 1.69, 95% CI 1.04-2.76)., Conclusions: In CCS patients without LM disease or reduced LVEF, physiology-guided PCI and CABG are associated with better outcomes than angiography-guided PCI. Compared with medical therapy, CABG is the only revascularization strategy associated with a reduction of myocardial infarction and death rates, at the cost of higher risk of stroke., Study Registration: This study is registered in PROSPERO (CRD42022313612)., Competing Interests: Declaration of Competing Interest M.G. declares that he has received consulting fees or honoraria from Terumo, outside the present work. D.C. declares that he has received consulting and speaker's fee from Amgen, Daiichi Sankyo, Sanofi, Tarumo outside the present work. G.B.-Z. has consulted for Cardionovum, CrannMed, InnovHeart, Meditrial, Opsens Medical, Replycare and Terumo, outside the present work. I.P. reports consultant or speaker fees from Biotronik, ABIOMED, Terumo, Philips, Sanofi, Amgen, Daiichi-Sankyo, Astra Zeneca, Bayer, and PIAM, outside the present work. F.B. declares that he has received consulting fees or honoraria from Abbott, Abiomed, Medtronic and Terumo, outside the present work. C.T. declares that he has received consulting fees or honoraria from Abbott, Abiomed, Medtronic and Terumo, outside the present work. R.DC. declares that he has received consulting fees or honoraria from Daiichi-Sankyo, Novartis, Roche, Boehringer Ingelheim, Bayer, BMS/Pfizer, Janssen, Novartis, AspraZeneca, Milestone, Lilly, Menarini, Guidotti, outside the present work. J.E. declares that he has participated as speaker at educational events and advisory board member for Abbott, Boston Scientific and Philips. D.J.A. declares that he has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, and Sanofi, outside the present work. D.J.A. also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions and Scott R. MacKenzie Foundation. F.C. declares that he has received consulting and speaker's fee from Amgen, AstraZeneca, Servier, BMS, outside the present work. F.C. also declares to be member of the advisory board of GlyCardial Diagnostics. The remaining authors report no disclosures., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: Pre-clinical congestion markers of worsening heart failure (HF) can be monitored by devices and may support the management of patients with HF. We aimed to assess whether congestion-guided HF management according to device-based remote monitoring strategies is more effective than standard therapy., Methods and Results: A comprehensive literature research for randomized controlled trials (RCTs) comparing device-based remote monitoring strategies for congestion-guided HF management versus standard therapy was performed on PubMed, Embase, and CENTRAL databases. Incidence rate ratios (IRRs) and associated 95% confidence intervals (CIs) were calculated using the Poisson regression model with random study effects. The primary outcome was a composite of all-cause death and HF hospitalizations. Secondary endpoints included the individual components of the primary outcome. A total of 4347 patients from eight RCTs were included. Findings varied according to the type of parameters monitored. Compared with standard therapy, haemodynamic-guided strategy (4 trials, 2224 patients, 12-month follow-up) reduced the risk of the primary composite outcome (IRR 0.79, 95% CI 0.70-0.89) and HF hospitalizations (IRR 0.76, 95% CI 0.67-0.86), without a significant impact on all-cause death (IRR 0.93, 95% CI 0.72-1.21). In contrast, impedance-guided strategy (4 trials, 2123 patients, 19-month follow-up) did not provide significant benefits., Conclusion: Haemodynamic-guided HF management is associated with better clinical outcomes as compared to standard clinical care., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Myocardial bridging (MB) is the most frequent congenital coronary anomaly in which a segment of an epicardial coronary artery takes a tunneled course under a bridge of the myocardium. This segment is compressed during systole, resulting in the so-called "milking effect" at coronary angiography. As coronary blood flow occurs primarily during diastole, the clinical relevance of MB is heterogeneous, being usually considered an asymptomatic bystander. However, many studies have suggested its association with myocardial ischemia, anginal symptoms, and adverse cardiac events. The advent of contemporary non-invasive and invasive imaging modalities and the standardization of intracoronary functional assessment tools have remarkably improved our understanding of MB-related ischemia, suggesting the role of atherosclerotic lesions proximal to MB, vasomotor disorders and microvascular dysfunction as possible pathophysiological substrates. The aim of this review is to provide a contemporary overview of the pathophysiology and of the non-invasive and invasive assessment of MB, in the attempt to implement a case-by-case therapeutic approach according to the specific endotype of MB-related ischemia., Competing Interests: Author MG declares that he has received consulting fees or honoraria from Terumo, outside the present work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ciliberti, Laborante, Di Francesco, Restivo, Rizzo, Galli, Canonico, Zito, Princi, Vergallo, Leone, Burzotta, Trani, Palmieri, Zeppilli, Crea and D’Amario.)

The incidence and clinical presentation of ischemic heart disease (IHD), as well as thrombotic and bleeding risks, appear to differ between genders. Compared with men, women feature an increased thrombotic risk, probably related to an increased platelet reactivity, higher level of coagulation factors, and sex-associated unique cardiovascular risk factors, such as pregnancy-related (i.e., pre-eclampsia and gestational diabetes), gynecological disorders (i.e., polycystic ovary syndrome, early menopause) and autoimmune or systemic inflammatory diseases. At the same time, women are also at increased risk of bleeding, due to inappropriate dosing of antithrombotic agents, smaller blood vessels, lower body weight and comorbidities, such as diabetes and chronic kidney disease. Pharmacological strategies focused on the personalization of antithrombotic treatment may, therefore, be particularly appealing in women in light of their higher bleeding and ischemic risks. Paradoxically, although women represent a large proportion of cardiovascular patients in our practice, adequate high-quality clinical trial data on women remain scarce and inadequate to guide decision-making processes. As a result, IHD in women tends to be understudied, underdiagnosed and undertreated, a phenomenon known as a "Yentl syndrome." It is, therefore, compelling for the scientific community to embark on dedicated clinical trials to address underrepresentation of women and to acquire evidence-based knowledge in the personalization of antithrombotic therapy in women., Competing Interests: Author MG was declares that he has received consulting fees or honoraria from Terumo, outside the present work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Laborante, Borovac, Galli, Rodolico, Ciliberti, Restivo, Cappannoli, Arcudi, Vergallo, Zito, Princi, Leone, Aurigemma, Romagnoli, Montone, Burzotta, Trani and D’Amario.)

Aims: The aims of this study is to assess by an updated meta-analysis the clinical outcomes related to permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation (TAVI) at long-term (≥12 months) follow-up (LTF)., Methods and Results: A comprehensive literature research was performed on PubMed and EMBASE. The primary endpoint was all-cause death. Secondary endpoints were rehospitalization for heart failure, stroke, and myocardial infarction. A subgroup analysis was performed according to the Society of Thoracic Surgeon-Predicted Risk of Mortality (STS-PROM) score. This study is registered with PROSPERO (CRD42021243301). A total of 51 069 patients undergoing TAVI from 31 observational studies were included. The mean duration of follow-up was 22 months. At LTF, PPI post-TAVI was associated with a higher risk of all-cause death [risk ratio (RR) 1.18, 95% confidence interval (CI) 1.10-1.25; P < 0.001] and rehospitalization for heart failure (RR 1.32, 95% CI 1.13-1.52; P < 0.001). In contrast, the risks of stroke and myocardial infarction were not affected. Among the 20 studies that reported procedural risk, the association between PPI and all-cause death risk at LTF was statistically significant only in studies enrolling patients with high STS-PROM score (RR 1.25, 95% CI 1.12-1.40), although there was a similar tendency of the results in those at medium and low risk., Conclusion: Patients necessitating PPI after TAVI have a higher long-term risk of all-cause death and rehospitalization for heart failure as compared to those who do not receive PPI., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Understanding the role of sex- and gender-related factors, when dealing with a global growing epidemic such as heart failure, is a much needed and unmet goal for health care providers and scientists in order to design targeted strategies, aimed at improving both clinical and patient reported outcomes measures in women and men with heart failure. The present review provides an overview of the current available evidence on sex- and gender-related differences in heart failure., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Necrotizing enterocolitis (NEC) is one of the most distressing gastrointestinal emergencies affecting neonates. Amniotic fluid stem cells (AFSC) improve intestinal injury and survival in experimental NEC but are difficult to administer. In this study, we evaluated whether conditioned medium (CM) derived from human AFSC have protective effects., Methods: Three groups of C57BL/6 mice were studied: (i) breast-fed mice as control; (ii) experimental NEC mice receiving PBS; and (iii) experimental NEC mice receiving CM. NEC was induced between post-natal days P5 through P9 via: (A) gavage feeding of hyperosmolar formula four-time a day; (B) 10 minutes hypoxia prior to feeds; and (C) lipopolysaccharide administration on P6 and P7. Intra-peritoneal injections of either PBS or CM were given on P6 and P7. All mice were sacrificed on P9 and terminal ileum were harvested for analyses., Results: CM treatment increased survival and reduced intestinal damage, decreased mucosal inflammation (IL-6; TNF-α), neutrophil infiltration (MPO), and apoptosis (CC3), and also restored angiogenesis (VEGF) in the ileum. Additionally, CM treated mice had increased levels of epithelial proliferation (Ki67) and stem cell activity (Olfm4; Lgr5) compared to NEC+PBS mice, showing restored intestinal regeneration and recovery during NEC induction. CM proteomic analysis of CM content identified peptides that regulated immune and stem cell activity., Conclusions: CM derived from human AFSC administered in experimental NEC exhibited various benefits including reduced intestinal injury and inflammation, increased enterocyte proliferation, and restored intestinal stem cell activity. This study provides the scientific basis for the use of CM derived from AFSC in neonates with NEC., Competing Interests: RM, SR, PD, and KP are stockholder of Micregen Ltd, this relationship had no effect on study design, analysis, or interpretation of results, and this does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors declared they had no conflict of interest.

Background: Recent trials demonstrated the clinical efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with heart failure (HF), regardless of the presence or absence of type 2 diabetes. These data may allow the use of this innovative drug class in clinical routine for treating these patients., Study Question: We aimed at further clarifying the role of SGLT2i in patients with diagnosis of HF, capitalizing on pooled sample size and heightened power for clinically relevant safety and efficacy outcomes., Data Sources: We conducted a systematic search of PubMed, reference lists of relevant articles, and Medline database from inception until March 1, 2021., Study Design: This meta-analysis was completed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched for randomized trials that evaluated the cardiovascular effects of SGLT2i in patients with HF. Three investigators independently assessed study eligibility, extracted the data, and assessed risk of bias. Hazard ratios and 95% confidence intervals (CIs) were pooled and meta-analyzed using a random-effect model. Numbers needed to treat (NNT) with the relative 95% CIs were also calculated. The primary outcome was a composite of HF hospitalization or an urgent visit for worsening HF and cardiovascular death., Results: Three trials were included in the study. Overall, treatment with SGLT2i was associated with a lower risk of the primary composite outcome [hazard ratios 0.73, 95% CI (0.67-0.80), NNT = 11.3]. Similarly, there was a significantly reduced risk of cardiovascular death, all-cause death, HF hospitalization and need for urgent treatment for HF, and HF hospitalization., Conclusions: Therefore, the available evidence supports the routine use of these drugs as standard-of-care, also given the highly favorable NNTs., Competing Interests: G. Biondi-Zoccai has consulted for Cardionovum, Innovheart, Meditrial, Opsens Medical, and Replycare. The reamining authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is increased in inflammatory bowel disease (IBD) patients, and its serum levels correlate with a worse prognosis. In the present manuscript, we show that eNAMPT serum levels are increased in IBD patients that fail to respond to anti-TNFα therapy (infliximab or adalimumab) and that its levels drop in patients that are responsive to these therapies, with values comparable with healthy subjects. Furthermore, eNAMPT administration in dinitrobenzene sulfonic acid (DNBS)-treated mice exacerbates the symptoms of colitis, suggesting a causative role of this protein in IBD. To determine the druggability of this cytokine, we developed a novel monoclonal antibody (C269) that neutralizes in vitro the cytokine-like action of eNAMPT and that reduces its serum levels in rodents. Of note, this newly generated antibody is able to significantly reduce acute and chronic colitis in both DNBS- and dextran sulfate sodium (DSS)-induced colitis. Importantly, C269 ameliorates the symptoms by reducing pro-inflammatory cytokines. Specifically, in the lamina propria, a reduced number of inflammatory monocytes, neutrophils, Th1, and cytotoxic T lymphocytes are found upon C269 treatment. Our data demonstrate that eNAMPT participates in IBD and, more importantly, that eNAMPT-neutralizing antibodies are endowed with a therapeutic potential in IBD. KEY MESSAGES: What are the new findings? Higher serum eNAMPT levels in IBD patients might decrease response to anti-TNF therapy. The cytokine-like activity of eNAMPT may be neutralized with a monoclonal antibody. Neutralization of eNAMPT ameliorates acute and chronic experimental colitis. Neutralization of eNAMPT limits the expression of IBD inflammatory signature. Neutralization of eNAMPT impairs immune cell infiltration in lamina propria.

Purpose: Activation of calcium/calmodulin-dependent protein kinase IV (CaMKIV) has been shown to increase intestinal injury and inhibit epithelial cell proliferation in dextran sulfate sodium (DSS)-induced colitis mice. However, the role of CaMKIV in necrotizing enterocolitis (NEC) is unknown. We aimed to study the expression and activation of CaMKIV in experimental NEC., Methods: Following ethical approval, NEC (n = 10) was induced in C57BL/6 mouse pups by hypoxia, gavage hyperosmolar formula feeding and lipopolysaccharide from postnatal days P5 to 9. Breastfed pups served as control (n = 10). Mouse pups were sacrificed on P9 and the terminal ileum was harvested. Gene NEC injury was scored blindly by three independent investigators. CaMKIV, CREM and IL17 gene expression, and CaMKIV and pCaMKIV protein expression were assessed. The data were compared using Mann-Whitney U test. P < 0.05 was considered significant., Results: Intestinal injury was induced in the NEC mice and confirmed by histological scoring and inflammatory cytokine IL6. CaMKIV and its downstream target genes of CREM and IL17 were significantly elevated in NEC mice relative to control. Similarly, phosphorylated-CaMKIV (pCaMKIV), the active form of CaMKIV, was more notably expressed in the NEC ileal tissue relative to control ileal tissue. Elevated pCaMKIV protein expression was also confirmed by western blot., Conclusion: CaMKIV expression and activation are upregulated in experimental NEC suggesting a potential contributing factor in the pathogenesis of NEC.

Understanding the role of sex- and gender-related factors, when dealing with a global growing epidemic such as heart failure, is a much needed and unmet goal for health care providers and scientists in order to design targeted strategies, aimed at improving both clinical and patient reported outcomes measures in women and men with heart failure. The present review provides an overview of the current available evidence on sex- and gender-related differences in heart failure., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This review focuses on the concept of antibodies acting as receptor agonists and antagonists, and on the potential relevance of this notion in applied medicine. Antibodies are composed of three functional units: two antigen-binding fragments (Fabs) that confer antigen specificity and one constant fragment (Fc) linking antibodies to immune effector functions. The proof-of-concept that large amounts of highly specific and homogeneous antibodies could be produced was provided in 1975 by César Milstein and Georges Köhler. These monoclonal antibody (mAb) reagents started a revolution in medical research, diagnostics, and clinical applications. Alongside diagnostic applications, mAbs were successfully used in vivo: (i) to bind (neutralize/antagonize) antigens expressed on the surface of tumor cells; (ii) to activate immune effector mechanisms; (iii) to crosslink plasma membrane receptors and hence activate therapeutic signaling pathways; and lastly, (iv) the technique was expanded to produce bispecific mAbs, which can bind two different antigens while retaining the ability to activate immune effector functions. The abilities of mAbs to bind, transduce signals, and exert immunostimulatory agonistic capacities are the central issues of this review. The starting point is that some mAbs operate as molecular agonists, substituting for the natural ligand of the receptor. Our analysis is restricted to mAbs that act as receptor agonist/antagonists by either mimicking ligand binding, or through allosteric modulation mediated by binding sites that are topographically distinct from the orthosteric binding site. Functional considerations based on the agonistic stimulation of human CD38 by specific mAbs as surrogate ligands are described as examples of the features of such molecules.

There is a real medical need of new diagnostic tools for the early recognition of invasive Candida infections. We exploited a rather simple and rapid redox methodology to construct a bispecific monoclonal antibody (bsmAb) that combines a monoclonal antibody (mAb) directed against 1,3-β-D-glucan, a well-known, pan-fungal diagnostic biomarker, with a mAb recognizing MP65, a major immunogenic mannoprotein secreted by C.albicans and other Candida species. The bsmAb (MP65/bglu mAb) was successfully produced and purified at high yields and proved to bind and reveal simultaneously, with high sensitivity, the β-glucan and MP65 antigens in both purified and native forms. The MP65/bglu mAb is the first bispecific antibody generated against a fungal microorganism and may prove useful for the concurrent detection of different and clinically significant Candida biomarkers in patient sera.

Surface functionalization with antitransferrin receptor (TfR) mAbs has been suggested as the strategy to enhance the transfer of nanoparticles (NPs) across the blood-brain barrier (BBB) and to carry nonpermeant drugs from the blood into the brain. However, the efficiency of BBB crossing is currently too poor to be used in vivo. In the present investigation, we compared 6 different murine mAbs specific for different epitopes of the human TfR to identify the best performing one for the functionalization of NPs. For this purpose, we compared the ability of mAbs to cross an in vitro BBB model made of human brain capillary endothelial cells (hCMEC/D3). Liposomes functionalized with the best performing mAb (MYBE/4C1) were uptaken, crossed the BBB in vitro, and facilitated the BBB in vitro passage of doxorubicin, an anticancer drug, 3.9 folds more than liposomes functionalized with a nonspecific IgG, as assessed by confocal microscopy, radiochemical techniques, and fluorescence, and did not modify the cell monolayer structural or functional properties. These results show that MYBE/4C1 antihuman TfR mAb is a powerful resource for the enhancement of BBB crossing of NPs and is therefore potentially useful in the treatment of neurologic diseases and disorders including brain carcinomas., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Nicotinamide adenine dinucleotide (NAD⁺) is an essential co-enzyme reported to operate both intra- and extracellularly. In the extracellular space, NAD⁺ can elicit signals by binding purinergic P2 receptors or it can serve as the substrate for a chain of ectoenzymes. As a substrate, it is converted to adenosine (ADO) and then taken up by the cells, where it is transformed and reincorporated into the intracellular nucleotide pool. Nucleotide-nucleoside conversion is regulated by membrane-bound ectoenzymes. CD38, the main mammalian enzyme that hydrolyzes NAD⁺, belongs to the ectoenzymatic network generating intracellular Ca(2+)-active metabolites. Within this general framework, the extracellular conversion of NAD⁺ can vary significantly according to the tissue environment or pathological conditions. Accumulating evidence suggests that tumor cells exploit such a network for migrating and homing to protected areas and, even more importantly, for evading the immune response. We report on the experience of this lab to exploit human multiple myeloma (MM), a neoplastic expansion of plasma cells, as a model to investigate these issues. MM cells express high levels of surface CD38 and grow in an environment prevalently represented by closed niches hosted in the bone marrow (BM). An original approach of this study derives from the recent use of the clinical availability of therapeutic anti-CD38 monoclonal antibodies (mAbs) in perturbing tumor viability and enzymatic functions in conditions mimicking what happens in vivo.

The tumor microenvironment is characterized by of high levels of extracellular nucleotides that are metabolized through the dynamic and sequential action of cell surface enzymes (ectoenzymes). These ectoenzymes operate according to their spatial arrangement, as part of (1) continuous (molecules on the same cell) or (2) discontinuous (molecules on different cells) pathways, the latter being facilitated by restricted cellular microenvironment. The outcome of this catabolic activity is an increase in the local concentration of adenosine, a nucleoside involved in the control of inflammation and immune responses. The aim of the work presented here was to demonstrate that a previously unexplored enzymatic pathway may be an alternate route to produce extracellular adenosine. Our data show that this new axis is driven by the nucleotide-metabolizing ectoenzymes CD38 (an NAD + nucleosidase), the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1, also known as CD203a or PC-1) and the 5' ectonucleotidase (5'-NT) CD73, while bypassing the canonical catabolic pathway mediated by the nucleoside tri- and diphosphohydrolase (NTPDase) CD39. To determine the relative contributions of these cell surface enzymes to the production of adenosine, we exploited a human T-cell model allowing for the modular expression of the individual components of this alternative pathway upon activation and transfection. The biochemical analysis of the products of these ectoenzymes by high-performance liquid chromatography (HPLC) fully substantiated our working hypothesis. This newly characterized pathway may facilitate the emergence of an adaptive immune response in selected cellular contexts. Considering the role for extracellular adenosine in the regulation of inflammation and immunogenicity, this pathway could constitute a novel strategy of tumor evasion, implying that these enzymes may represent ideal targets for antibody-mediated therapy.