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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: Carriers of cytochrome 2C19 (CYP2C19) loss-of-function (LoF) alleles treated with clopidogrel have impaired drug metabolism, resulting in reduced active metabolite levels, high platelet reactivity (HPR), and an increased risk of thrombotic events. Several alternative antiplatelet therapies have been proposed to overcome HPR in these patients, but their comparative effects remain poorly explored., Methods: Randomized controlled trials (RCTs) comparing different oral antiplatelet therapies in carriers of CYP2C19 LoF alleles undergoing percutaneous coronary interventions (PCI) were included. A frequentist network meta-analysis was conducted to estimate mean difference (MD) or odds ratios and 95% confidence intervals (CI). The primary outcome was platelet reactivity assessed by VerifyNow and reported as P2Y12 reaction unit (PRU). The secondary outcome was the rate of HPR. Standard dose of clopidogrel (75 mg daily) was used as a reference treatment., Results: A total of 12 RCTs testing 6 alternative strategies (i.e. clopidogrel 150 mg, prasugrel 3.75 mg, 5 mg, and 10 mg, ticagrelor 90 mg bid, and adjunctive cilostazol 100 mg bid) were included in the network. Compared with standard-dose clopidogrel, the greatest reduction in PRU was observed with prasugrel 10 mg (MD -127.91; 95% CI -141.04; -114.78) and ticagrelor 90 mg bid (MD -124.91; 95% CI -161.78; -88.04), followed by prasugrel 5 mg (MD -76.33; 95% CI -98.01; -54.65) and prasugrel 3.75 mg (MD -73.00; 95% CI -100.28; -45.72). Among other strategies, adjunctive cilostazol (MD -42.64; 95% CI -64.72; -20.57) and high-dose clopidogrel (MD -32.11; 95% CI -51.33; -12.90) were associated with a modest reduction in PRU compared with standard-dose clopidogrel., Conclusion: Among carriers of CYP2C19 LoF alleles undergoing PCI, standard-dose prasugrel or ticagrelor are most effective in reducing platelet reactivity, while double-dose clopidogrel and additional cilostazol showed modest effects. Reduced-dose of prasugrel may represent a balanced strategy to overcome HPR without a significant increase in bleeding. The clinical implications of these pharmacodynamic findings warrant further investigation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Several repair strategies emerged as possible treatment for severe mitral regurgitation (MR). A systematic review and meta-analysis was performed to compare the different percutaneous mitral valve repair approaches., Methods: PubMed and Scopus electronic databases were scanned for eligible studies until December 11th, 2023. Clinical efficacy endpoints were all-cause mortality, major adverse cardiovascular events, and post-procedural NYHA functional class <3; the echocardiographic efficacy endpoint was a post-intervention residual MR less than moderate. Safety endpoints and procedural outcome measures were also assessed., Results: Eleven studies were included: 8 [N = 1662 patients, mean follow-up (FUP) 294 days] compared MitraClip® vs Pascal® device, 2 (N = 195 patients) MitraClip® vs Carillon® and 1 study (N = 186 patients) evaluated MitraClip® against Cardioband®. The Pascal®-treated group had lower MR degree compared to the MitraClip®-treated group, without difference in post-intervention mean trans-mitral gradient and in clinical and safety endpoints. A longer procedure time was observed in the Pascal® group, albeit with a lower average number of implanted devices per procedure. The two studies comparing MitraClip® and Carillon® were inconsistent in terms of both efficacy and safety outcomes, while the study evaluating MitraClip® vs Cardioband® showed that the latter might confer a significant clinical benefit, with a similar reduction in MR., Conclusions: Pascal® is as safe and clinically effective as MitraClip® in treating patients with MR, with an apparent greater reduction in the magnitude of residual valve insufficiency over the long term. Data on Cardioband® and Carillon® are not robust enough to draw conclusions from the use of such devices., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare for the present work., (Copyright © 2024. Published by Elsevier B.V.)

Aims: Several mechanisms have been identified in the aetiopathogenesis of heart failure with preserved ejection fraction (HFpEF). Among these, coronary microvascular dysfunction (CMD) may play a key pathophysiological role. We performed a systematic review and meta-analysis to investigate the prevalence, echocardiographic correlates, and prognostic implications of CMD in patients with HFpEF., Methods and Results: A systematic search for articles up to 1 May 2023 was performed. The primary aim was to assess the prevalence of CMD. Secondary aims were to compare key echocardiographic parameters (E/e' ratio, left atrial volume index [LAVi], and left ventricular mass index [LVMi]), clinical outcomes [death and hospitalization for heart failure (HF)], and prevalence of atrial fibrillation (AF) between patients with and without CMD. Meta-regressions according to baseline patient characteristics and study features were performed to explore potential heterogeneity sources. We identified 14 observational studies, enrolling 1138 patients with HFpEF. The overall prevalence of CMD was 58%. Compared with patients without CMD, patients with HFpEF and CMD had larger LAVi [mean difference (MD) 3.85 confidence interval (CI) 1.19-6.5, P < 0.01)], higher E/e' ratio (MD 2.76 CI 1.54-3.97; P < 0.01), higher prevalence of AF (odds ratio 1.61 CI 1.04-2.48, P = 0.03) and higher risk of death or hospitalization for HF [hazard ratio 3.19, CI 1.04-9.57, P = 0.04]., Conclusions: CMD is present in little more than half of the patients with HFpEF and is associated with echocardiographic evidence of more severe diastolic dysfunction and a higher prevalence of AF, doubling the risk of death or HF hospitalization., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Ticagrelor improves clinical outcomes in patients with acute coronary syndromes compared with clopidogrel. Ticagrelor also inhibits cell uptake of adenosine and has been associated with cardioprotective effects in animal models. We sought to investigate the potential cardioprotective effects of ticagrelor, as compared with clopidogrel, in stable patients undergoing percutaneous coronary intervention (PCI)., Methods and Results: This was a Prospective Randomized Open Blinded End-points (PROBE) trial enrolling stable patients with coronary artery disease (CAD) requiring fractional flow reserve-guided PCI of intermediate epicardial coronary lesions. ST-segment elevation at intracoronary electrocardiogram (IC-ECG) during a two-step sequential coronary balloon inflations in the reference vessel during PCI was used as an indirect marker of cardioprotection induced by ischemic preconditioning (IPC). The primary endpoint of the study was the comparison of the delta (Δ) (difference) ST-segment elevation measured by IC-ECG during two-step sequential coronary balloon inflations., Results: Fifty-three patients were randomized to either clopidogrel or ticagrelor. The study was stopped earlier because the primary endpoint was met at a pre-specified interim analysis. ΔST-segment elevation was significantly higher in ticagrelor as compared to clopidogrel arms (P < 0.0001). Ticagrelor was associated with lower angina score during coronary balloon inflations. There was no difference in coronary microvascular resistance between groups. Adenosine serum concentrations were increased in patients treated with ticagrelor as compared to those treated with clopidogrel., Conclusions: Ticagrelor enhances the cardioprotective effects of IPC compared with clopidogrel in stable patients with CAD undergoing PCI. Further studies are warranted to fully elucidate the mechanisms through which ticagrelor may exert cardioprotective effects in humans., Clinical Trial Registration: http://www.clinicaltrials.gov. Unique Identifier: NCT02701140., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Randomized controlled trials (RCTs) testing bleeding reduction strategies using antiplatelet treatment regimens (BRATs) in acute coronary syndromes (ACS) have shown promising results, but the generalizability of these findings may be significantly influenced by the ethnicity of the patients enrolled, given that East Asian (EA) patients show different ischaemic-bleeding risk profile compared to non-EA patients., Methods and Results: RCTs comparing a BRAT vs. standard 12-month dual antiplatelet therapy (DAPT) in patients with ACS undergoing percutaneous coronary intervention (PCI) were selected. The primary efficacy endpoint was major adverse cardiovascular events (MACE) as defined in each trial and the primary safety endpoint was minor or major bleeding. Twenty-six RCTs testing seven different BRATs were included. The only strategy associated with a trade-off in MACE was 'upfront unguided de-escalation' in the subgroup of non-EAs (risk ratio 1.16, 95% confidence interval 1.09-1.24). All but aspirin monotherapy-based strategies (i.e. 'short and very short DAPT followed by aspirin') were associated with reduced bleeding compared with standard DAPT in both EA and non-EA patients. There were no significant differences between subgroups, but the lack of RCTs in some of the included strategies and the difference in the certainty of evidence between EA and non-EA patients revealed that the evidence in support of different BRATs in ACS undergoing PCI is influenced by ethnicity. Moreover, absolute risk reduction estimation revealed that some BRATs might be more effective than others in reducing bleeding according to ethnicity., Conclusion: The majority of BRATs are associated with reduced bleeding without any trade-off in hard ischaemic endpoints regardless of ethnicity. However, the supporting evidence and relative safety profiles of different BRATs might be significantly affected by ethnicity, which should be taken into account in clinical practice., Study Registration: This study is registered in PROSPERO (CRD42023416710)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Routine thrombus aspiration (TA) does not improve clinical outcomes in patients with ST-segment-elevation myocardial infarction (STEMI), although data from meta-analyses suggest that patients with high thrombus burden may benefit from it. The impact of TA on left ventricular (LV) functional recovery and remodeling after STEMI remains controversial. We aimed to pool data from randomized controlled trials (RCTs) on the impact of TA on LV function and remodeling after primary percutaneous coronary intervention (pPCI)., Methods: PubMed and CENTRAL databases were scanned for eligible studies. Primary outcome measures were: LV ejection fraction (LVEF), LV end diastolic volume (LVEDV), LV end systolic volume (LVESV) and wall motion score index (WMSI). A primary pre-specified subgroup analysis was performed comparing manual TA with mechanical TA., Results: A total of 28 studies enrolling 4990 patients were included. WMSI was lower in TA group than in control (mean difference [MD] -0.11, 95% confidence interval [CI] -0.19 to -0.03). A greater LVEF (MD 1.91, 95% CI 0.76 to 3) and a smaller LVESV (MD -6.19, 95% CI -8.7 to -3.6) were observed in manual TA group compared to control. Meta regressions including patients with left anterior descending artery (LAD) involvement showed an association between TA use and the reduction of both LVEDV and LVESV (z = -2.13, p = 0.03; z = -3.7, p < 0.01) and the improvement in myocardial salvage index (z = 2.04, p = 0.04)., Conclusion: TA is associated with improved LV function. TA technique, total ischemic time and LAD involvement appears to influence TA benefit on post-infarction LV remodeling., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Cardiotoxicity occurs in 5-20% of cancer patients who receive anthracyclines. The aim of this study was to pool all the randomized controlled trials (RCTs) investigating the cardio-protective role of statins in patients treated with anthracyclines., Methods: PubMed and Scopus electronic databases were scanned for eligible studies up to May 3rd, 2023. A total of 5 RCTs with 808 patients were included. Efficacy endpoints were the rate of anthracycline-mediated cardiotoxicity, the incidence of hospitalization for heart failure (HF), left ventricular ejection fraction (LVEF) value after anthracycline treatment, and ∆LVEF calculated as the difference in LVEF before and after anthracycline therapy. Safety endpoints [i.e., the incidence of muscle pain and serious adverse events (SAE)] were also assessed., Results: On pooled analysis, the statin-treated group had a lower incidence of cardiotoxicity compared to the placebo group [risk ratio (RR) 0.52, 95% confidence Interval (CI) 0.33-0.83, P = 0.01; I 2  = 0%], as well as higher mean LVEF [Mean difference (MD) 1.88, 95% CI 0.66-3.1, P < 0.01; I 2  = 57.3%)] and a more favorable ∆LVEF during follow-up (MD 2.38, 95% CI -0.03 - +4.79, P = 0.05; I 2  = 99%), despite no significant difference in terms of hospitalization for HF and rate of adverse events. Of note, severe heterogeneity affected the analyses for both LVEF and ΔLVEF., Conclusions: The current meta-analysis of all RCTs conducted so far shows an overall beneficial effect of statins on the risk of anthracyclines-induced cardiotoxicity and LVEF preservation. No difference was observed in the rate of HF hospitalization. More powered RCTs are needed to fully investigate the impact of statins on prognosis in patients receiving anthracyclines therapy., Competing Interests: Declaration of Competing Interest M.G. declares that he has received consulting fees or honoraria from Terumo, outside the present work. The other authors have no conflicts of interest to declare for the present work., (Copyright © 2023. Published by Elsevier B.V.)

Chest pain affects more than 100 million people globally, however up to 70% of patients undergoing invasive angiography do not have obstructive coronary artery disease and ischemia with non-obstructive coronary artery disease (INOCA) is often a cause of the clinical picture. The symptoms reported by INOCA patients are very heterogeneous and often misdiagnosed as non-cardiac leading to under-diagnosis/investigation and under-treatment. The underlying pathophysiological mechanisms of INOCA are multiple and include coronary vasospasm and microvascular dysfunction. Most importantly, this condition must not be considered benign: compared to asymptomatic individuals, INOCA patients present an increased incidence of cardiovascular events, rehospitalizations, as well as impaired quality of life, with increasing costs for healthcare systems. The aims of this review are to describe the pathophysiological and clinical characteristics of INOCA and to provide guidance to the medical community on the diagnostic approaches and management of INOCA, also via a series of clinical case reports.

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:  Phase II randomized controlled trials (RCTs) on factor(F)XI inhibitors have shown promising results but they were burdened by low statistical power for clinical outcomes., Methods:  We performed a systematic review and meta-analysis of RCT comparing FXI inhibitors versus other anticoagulants (enoxaparin or direct oral anticoagulants, DOACs) or versus placebo on top of antiplatelet therapy., Results:  Eight RCTs testing FXI inhibitors (ISIS 416858, osocimab, abelacimab, milvexian, asundexian) and enrolling 9,216 patients were included. Compared with enoxaparin, FXI inhibitors were associated with reduced any-bleeding (risk ratio [RR]: 0.49, 95% confidence interval [CI]: 0.31-0.77), no difference in major bleeding (RR: 0.96, 95% CI: 0.41-2.28), and reduced trial-defined efficacy endpoint (RR: 0.62, 95% CI: 0.49-0.79), the latter driven by the high-dose regimens. Compared with DOACs, FXI inhibitors were associated with a trend toward reduced any-bleeding (RR: 0.66, 95% CI: 0.31-1.38) and no difference in major bleeding (RR: 1.03, 95% CI: 0.22-4.78) or in trial-defined efficacy endpoint (RR: 1.23, 95% CI: 0.88-1.70). Compared with placebo, FXI inhibitors were associated with increased any-bleeding (RR: 1.25, 95% CI: 1.08-1.43) and a trend toward increased major bleeding (RR: 1.21, 95% CI: 0.75-1.93), both driven by high-dose regimens, with no difference in trial-defined efficacy endpoint (RR: 1.02, 95% CI: 0.92-1.13)., Conclusion:  Results of this meta-analysis on FXI inhibitors suggest increased safety and efficacy compared with enoxaparin and modest increased safety compared with DOACs. The use of FXI inhibitors in adjunct to antiplatelet therapy versus placebo appears to be associated with a dose-dependent increase in bleeding without any difference in efficacy., Study Registration:  This study is registered in PROSPERO (CRD42022367706)., Competing Interests: M.G. declares that he has received consulting fees or honoraria from Terumo, outside the present work. F.F. declares that he has received payment as an individual for consulting fee or honoraria from AstraZeneca, Bayer, and Sanofi, and institutional payments for grants from PLx Pharma and The Scott R. MacKenzie Foundation. D.C. declares that he has received consulting and speaker's fee from Amgen, Daiichi Sankyo, Sanofi, and Terumo outside the present work. C.M.G. has received research grant support from Angel Medical Corporation, Bayer Corp, CSL Behring, Janssen Pharmaceuticals, Johnson & Johnson Corporation, and Portola Pharmaceuticals, and has received modest consulting monies from Amarin Pharma, Amgen, Arena Pharmaceuticals, Bayer Corporation, Boehringer Ingelheim, Boston Clinical Research Institute, Cardiovascular Research Foundation, Chiesi, CSL Behring, Eli Lilly, Gilead Sciences, Inc, Janssen Pharmaceuticals, Johnson & Johnson Corporation, The Medicines Company, Merk & Co, Inc., Novo Nordisk, Pfizer, Pharma Mar, Portola Pharmaceuticals, Sanofi, Somahlution, St. Francis Hospital, Verson Corporation, and Web MD. R.M. reports the following outside of the submitted work: institutional research payments from Abbott, Abiomed, Alleviant Medical, AM‐Pharma, Amgen, Arena, AstraZeneca, Atricure, Bayer, Biosensors, Biotronik, Boston Scientific, Bristol‐Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi Sankyo, Element Science, Faraday, Humacyte, Idorsia Pharmaceuticals, Janssen, Medtronic, Novartis, OrbusNeich, PhaseBio, Philips, Pi‐Cardia, RenalPro, Shockwave, Vivasure, and Zoll; personal fees from Cine‐Med Research and WebMD; equity <1% in Applied Therapeutics, Elixir Medical, Stel, and ControlRad (spouse); Scientific Advisory Board for American Medical Association, American College of Cardiology (Board of Trustees Member), Society for Cardiovascular Angiography and Interventions (Women in Innovations Committee Member), and JAMA Associate Editor; and Faculty Cardiovascular Research Foundation (no fee). 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, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi and Ventura, 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. The remaining authors report no disclosures., (Thieme. All rights reserved.)

Background: Heart failure (HF) is a multifaceted clinical syndrome characterized by different etiologies, risk factors, comorbidities, and a heterogeneous clinical course. The current model, based on data from clinical trials, is limited by the biases related to a highly-selected sample in a protected environment, constraining the applicability of evidence in the real-world scenario. If properly leveraged, the enormous amount of data from real-world may have a groundbreaking impact on clinical care pathways. We present, here, the development of an HF DataMart framework for the management of clinical and research processes., Methods: Within our institution, Fondazione Policlinico Universitario A. Gemelli in Rome (Italy), a digital platform dedicated to HF patients has been envisioned (GENERATOR HF DataMart), based on two building blocks: 1. All retrospective information has been integrated into a multimodal, longitudinal data repository, providing in one single place the description of individual patients with drill-down functionalities in multiple dimensions. This functionality might allow investigators to dynamically filter subsets of patient populations characterized by demographic characteristics, biomarkers, comorbidities, and clinical events (e.g., re-hospitalization), enabling agile analyses of the outcomes by subsets of patients. 2. With respect to expected long-term health status and response to treatments, the use of the disease trajectory toolset and predictive models for the evolution of HF has been implemented. The methodological scaffolding has been constructed in respect of a set of the preferred standards recommended by the CODE-EHR framework., Results: Several examples of GENERATOR HF DataMart utilization are presented as follows: to select a specific retrospective cohort of HF patients within a particular period, along with their clinical and laboratory data, to explore multiple associations between clinical and laboratory data, as well as to identify a potential cohort for enrollment in future studies; to create a multi-parametric predictive models of early re-hospitalization after discharge; to cluster patients according to their ejection fraction (EF) variation, investigating its potential impact on hospital admissions., Conclusion: The GENERATOR HF DataMart has been developed to exploit a large amount of data from patients with HF from our institution and generate evidence from real-world data. The two components of the HF platform might provide the infrastructural basis for a combined patient support program dedicated to continuous monitoring and remote care, assisting patients, caregivers, and healthcare professionals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 D'Amario, Laborante, Delvinoti, Lenkowicz, Iacomini, Masciocchi, Luraschi, Damiani, Rodolico, Restivo, Ciliberti, Paglianiti, Canonico, Paternello, Cesario, Valentini, Scambia and Crea.)

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 and Aims: Edoxaban proved to be safe and effective also in fragile patients, but its administration through percutaneous endoscopic gastrostomy (PEG) has not been previously investigated. The purpose of this study was to evaluate the feasibility and the preliminary safety and efficacy profiles of edoxaban administered via PEG in patients with an indication for long-term oral anticoagulation., Methods: ORIGAMI was a prospective, single-arm, observational study (NCT04271293). Patients with PEG and an indication for long-term anticoagulation were prospectively enrolled. Crushed edoxaban at approved doses was administered via PEG. The primary endpoint was the composite of cardio-embolic events consisting of ischemic stroke, systemic embolism, or symptomatic deep venous thrombosis/pulmonary embolism (DVT/PE). Secondary endpoints were the number of bleeding events and edoxaban plasma concentrations at steady state. We here report the 12-month results., Results: A total of 12 patients were enrolled. The main indication for PEG implantation was amyotrophic lateral sclerosis (10/12). The primary endpoint of cardio-embolic events did not occur in any patients at 12 months. All patients were in the therapeutic range of steady-state edoxaban plasma levels. Three minor bleedings were observed, while no major bleedings occurred during the observational period. A total of five patients died. All deaths were from non-cardiovascular causes and were consistent with the natural history of the pre-existing severe disease., Conclusion: Our study suggests that edoxaban administration via PEG is feasible and appears safe and effective in fragile, comorbid patients, resulting in therapeutic plasma concentrations of edoxaban., Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT04271293]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cappannoli, Laborante, Galli, Canonico, Ciliberti, Restivo, Princi, Arcudi, Sabatelli, De Cristofaro, Crea and D’Amario.)

Myocardial bridge (MB) is the most frequent inborn coronary artery variant in which a portion of the myocardium overlies an epicardial coronary artery segment. Although MB has long been considered a benign entity, a growing body of evidence has suggested its association with angina and adverse cardiac events. However, to date, no data on long-term prognosis are available, nor on therapies improving cardiovascular outcomes. We are currently conducting an ambispective, observational, multicentre, study in which we enrol patients with a clinical indication to undergo coronary angiography (CA) and evidence of MB, aiming to describe the incidence of symptoms and cardiovascular events at baseline and at long-term follow-up (FUP). The role of invasive full-physiology assessment in modifying the discharge therapy and eventually the perceived quality of life and the incidence of major cardiovascular events will be analysed. Basal clinical-instrumental data of eligible and consenting patients have been acquired after CA; FUP was performed 6, 12, and 24 months after the angiographic diagnosis of MB. The primary endpoint of the study is the incidence of major adverse cardiovascular events (MACE), defined as the composite of cardiac death, myocardial infarction, cardiac hospitalization, and target vessel revascularization; the secondary endpoints are the rate of patients with Seattle Angina Questionnaire (SAQ) summary score <70 and the incidence of MACE in patients undergoing invasive intracoronary assessment. Among patients undergone FUP visits, we recorded 31 MACE at 6 months (11.6%), 16 MACE at 12 months (6.5%), and 26 MACE at 24 months (13.5%). The rate of patients with SAQ <70 is 18.8% at 6 months, 20.6% at 12 months, and 21.8% at 24 months. To evaluate the prognostic role of invasive intracoronary assessment, we compared MB patients who underwent only angiographic evaluation (Angio group) to those who underwent acetylcholine (ACH) provocative test with indication to calcium-channel blockers (CCBs) at discharge (Angio + ACH + CCBs group) and those who underwent functional assessment with fractional flow reserve (FFR) with indication to beta-blockers (BBs) at discharge (Angio + FFR + BBs group). After 2 years of FUP, the rate of MACE was significantly reduced in both Angio + ACH + CCBs group (6 vs. 25%, P = 0.029) and Angio + FFR + BBs group (3 vs. 25%, P = 0.005) compared with Angio group. The preliminary results of our study showed that MB may be a cause of angina and adverse cardiac events in patients referred to CA for suspected coronary artery disease (CAD). Full-physiology assessment unmasking MB-related ischaemia mechanisms, allowed to guide the treatment, personalizing the clinical management, improving the quality of life, and cardiovascular outcomes in patients with MB., Competing Interests: Conflicts of interest: All authors have no conflicts of interest to declare., (© The Author(s) 2022. Published by Oxford University Press on behalf of the 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.)

Percutaneous coronary intervention (PCI) is considered a relatively safe procedure associated with low rates of complications, but is inevitably associated with short and mid-to-long term increased bleeding risk. Besides the short term risk associated with the arterial access to perform PCI, enhanced bleeding risk persists for several months, given the need for antithrombotic therapy to prevent procedure-related thrombotic complications as well as ischemic recurrences. Bleeding is a powerful harbinger of adverse outcomes. This awareness has fuelled intense research on bleeding reduction strategies, including new PCI devices and techniques as well as new medications and antithrombotic regimens. We here review the mechanisms and prevalence of bleeding in PCI patients, discuss the available evidence from a practical point of view, and explore future perspectives on how to treat and prevent bleeding complications in these patients., Competing Interests: M.G. declares that he has received consulting fees or honoraria from Terumo, outside the present work. F.A. declares that she has received consulting fees or honoraria from AstraZeneca, Amgen, Bayer, BMS/Pfizer and Daiichi-Sankyo, 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. F.C. declares to be member of the advisory board of GlyCardial Diagnostics. The remaining authors report no disclosures. Mattia Galli is serving as one of the Guest editors of this journal. We declare that Mattia Galli had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Julio Núñez Villota., (Copyright: © 2022 The Author(s). Published by IMR Press.)

Background: Despite continuous advancement in the field, heart failure (HF) remains the leading cause of hospitalization among the elderly and the overall first cause of hospital readmission in developed countries. Implantable hemodynamic monitoring is being tested to anticipate the clinical exacerbation onset, potentially preventing an emergent acute decompensation. To date, only pulmonary artery pressure (PAP) sensor received the approval to be implanted in symptomatic heart failure patients with reduced ejection fraction. However, PAP's indirect estimation of left ventricular filling pressure can be inaccurate in some contexts., Methods: The VECTOR-HF study (NCT03775161) is examining the safety, usability and performance of the V-LAP system, a latest-generation device capable of continuously monitoring left atrial pressure (LAP). In our center, five advanced HF patients have been enrolled. After confirmation of the transmitted data reliability, LAP trends and waveforms have guided therapy optimization. The aim of this work is to share clinical insights from our center preliminary experience with V-LAP application., Results: Over a median follow-up time of 18 months, LAP-based therapy optimization managed to reduce intracardiac pressure over time and no hospital readmission occurred. This result was paralleled by an improvement in both functional capacity (6MWT distance 352.5 ± 86.2 meters at baseline to 441.2 ± 125.2 meters at last follow-up) and quality of life indicators (KCCQ overall score 63.82 ± 16.36 vs. 81.92 ± 9.63; clinical score 68.47 ± 19.48 vs. 83.70 ± 15.58)., Conclusion: Preliminary evidence from V-LAP application at our institution support a promising efficacy. However, further study is needed to confirm the technical reliability of the device and to exploit the clinical benefit of left-sided hemodynamic remote monitoring., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Restivo, D'Amario, Paglianiti, Laborante, Princi, Cappannoli, Iaconelli, Galli, Aspromonte, Locorotondo, Burzotta, Trani and Crea.)

New direct oral anticoagulants are recommended for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). However, no data are available regarding the optimal time to start oral anticoagulation after acute stroke. The aim of our study was to evaluate the occurrence of symptomatic bleedings within 90 days from acute cardioembolic stroke in patients who received early treatment with Edoxaban. The study was conducted according to an observational prospective uncontrolled design. Secondary endpoints were the incidence of major bleeding (MB), hemorrhagic transformation within the first week of Edoxaban treatment, minor bleeding, and recurrent stroke. We included patients with Alberta Stroke Program Early Computed Tomography Score (ASPECTS) ≥ 6, NVAF, no previous treatment with any other anticoagulant, preserved swallowing function. Patients with estimated Glomerular Filtration Rate < 50 mL/min, body weight < 60 kg, receiving cyclosporine, dronedarone, erythromycin, ketoconazole, or previous treatment with any other anticoagulant were excluded. We enrolled 75 elderly patients with moderate disability. We did not observe any symptomatic intracranial bleeding or recurrent stroke after 3 months of treatment with early administration of Edoxaban, while two gastrointestinal MB, and 11 minor bleedings were reported. Asymptomatic bleeding was evaluated with a brain Magnetic Resonance Imaging performed 5 days after starting anticoagulant treatment with Edoxaban. Specifically, we observed small petechiae in 12% of the patients, confluent petechiae in 6.6% of the patients, and small hematoma of the infarcted area in 2.7% of the patients. No intralesional hematoma or hemorrhagic lesion outside the infarcted area were observed. According to our data, the early use of Edoxaban seems to be safe in patients after cardioembolic stroke. However, due to the small size of the study sample, and the short follow-up period, further studies are needed.