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In the period of increasing prevalence of metabolic disorders such as obesity and diabetes, healthcare professionals are facing significant challenges. Therefore, an accurate global assessment of insulin resistance is of utmost importance. Current medical research is focused on identifying an easily accessible and reproducible gold-standard surrogate marker for insulin resistance. Ideally, such a marker would enable healthcare providers to predict the risk of type 2 diabetes and cardiovascular diseases. The triglyceride-glucose index (TyG) is a promising marker for preventive cardiology and cardiometabolic medicine. This narrative review article aims to provide a comprehensive evaluation of the credibility of TyG as a surrogate marker of insulin resistance among patients at different stages across the cardiometabolic continuum. This assessment fully complies with evidence-based medicine and offers valuable insight into the clinical utility of TyG., Competing Interests: Declaration of competing interest Epson., (Copyright © 2024. Published by Elsevier B.V.)

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.)

Chronic smokers have increased risk of fibrosis-related atrial fibrillation. The use of heated-tobacco products (HTPs) is increasing exponentially, and their health impact is still uncertain. We aim to investigate the effects of circulating molecules in exclusive HTP chronic smokers on the fibrotic behavior of human atrial cardiac stromal cells (CSCs). CSCs were isolated from atrial tissue of elective cardiac surgery patients, and exposed to serum lots from young healthy subjects, stratified in exclusive HTP smokers, tobacco combustion cigarette (TCC) smokers, or nonsmokers (NS). CSCs treated with TCC serum displayed impaired migration and increased expression of pro-inflammatory cytokines. Cells cultured with HTP serum showed increased levels of pro-fibrotic markers, and reduced expression of connexin-43. Both TCC and HTP sera increased collagen release and reduced secretion of angiogenic protective factors from CSCs, compared to NS serum. Paracrine support to tube-formation by endothelial cells and to viability of cardiomyocytes was significantly impaired. Treatment with sera of both smokers groups impaired H 2 O 2 /NO release balance by CSCs and reduced early phosphorylation of several pathways compared to NS serum, leading to mTOR activation. Cotreatment with rapamycin was able to reduce mTOR phosphorylation and differentiation into aSMA-positive myofibroblasts in CSCs exposed to TCC and HTP sera. In conclusion, the circulating molecules in the serum of chronic exclusive HTP smokers induce fibrotic behavior in CSCs through activation of the mTOR pathway, and reduce their beneficial paracrine effects on endothelial cells and cardiomyocytes. These results point to a potential risk for cardiac fibrosis in chronic HTP users., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Giuseppe Biondi-Zoccai reports a relationship with Cardionovum, Crannmedical, Innovheart, Meditrial, Opsens Medical, Replycare, and Terumo that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Minimizing the use of blood component can reduce known and unknown blood transfusion risks, preserve blood bank resources, and decrease healthcare costs. Red Blood Cell (RBC) transfusion is common after cardiac surgery and associated with adverse perioperative outcomes, including mortality. Acute normovolemic hemodilution (ANH) may reduce bleeding and the need for blood product transfusion after cardiac surgery. However, its blood-saving effect and impact on major outcomes remain uncertain., Methods: This is a single-blinded, multinational, pragmatic, randomized controlled trial with a 1:1 allocation ratio conducted in Tertiary and University hospitals. The study is designed to enroll patients scheduled for elective cardiac surgery with planned cardiopulmonary bypass (CPB). Patients are randomized to receive ANH before CPB or the best available treatment without ANH. We identified an ANH volume of at least 650 ml as the critical threshold for clinically relevant benefits. Larger ANH volumes, however, are allowed and tailored to the patient's characteristics and clinical conditions., Results: The primary outcome is the percentage of patients receiving RBCs transfusion from randomization until hospital discharge, which we hypothesize will be reduced from 35% to 28% with ANH. Secondary outcomes are all-cause 30-day mortality, acute kidney injury, bleeding complications, and ischemic complications., Conclusion: The trial is designed to determine whether ANH can safely reduce RBC transfusion after elective cardiac surgery with CPB., Study Registration: This trial was registered on ClinicalTrials.gov in April 2019 with the trial identification number NCT03913481., Competing Interests: Declaration of competing interest 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. Three authors specified the following financial interests even if not related to this paper: Dr Ranucci declares the following financial interests: CSL Behring, Haemonetics, LFB, Werfen, Grifols. Dr Guarracino declares the following financial interests: Abbott, AOP Orphan, Edwards, Masimo, Orion, Viatris Dr Mazzeffi declares the following financial interests: consulting fees from Octapharma, Hemosonics, NovoNordisk, (Copyright © 2024. Published by Elsevier Inc.)

Background: Interleukin-1 blockade with anakinra reduces C-reactive protein (CRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). The effectiveness of anakinra according to the degree of systemic inflammation in STEMI has not been addressed., Methods: We analyzed 139 patients from three Virginia Commonwealth University Anakinra Response Trial randomized clinical trials to assess whether CRP levels predicted HF hospitalization or death in patients with STEMI, and if CRP levels influenced the effects of treatment with anakinra., Results: CRP cut-off levels for prediction of the composite of death or HF hospitalization for CRP at admission, 3 and 14 days were, respectively 6.45 mg/L (100% of sensitivity and 66.1% specificity), 26 mg/L (100% of sensitivity and 78% specificity) and 9.56 mg/L (100% of sensitivity and 80% specificity). More patients with elevated CRP levels died or had a HF hospitalization (5/47 [11%] vs 0/82 [0%], p = 0.004 for CRP at admission; 5/32 [15.6%] vs 0/92 [0%], p < 0.001 for day 3 and 5/26 [19%] vs 0/89 [0%], p < 0.001 for day 14). A greater number of patients treated with anakinra had low CRP levels at 3 and 14 days compared to placebo (Odds Ratio 0.11 [95% IC 0.04-0.28], p < 0.0001 and OR 0.35 [95% CI 0.14-0.86], p = 0.02, respectively). Anakinra significantly prevented death or HF hospitalization in patients with high inflammatory burden (p = 0.04 for admission, p = 0.24 for day 3, and p = 0.05 for day 14)., Conclusion: Patients with elevated CRP had higher incidence of HF hospitalization or death. Anakinra reduced the number of patients with elevated CRP levels and prevented death or HF hospitalization in patients with elevated CRP levels., Competing Interests: Declaration of Competing Interest Dr. Abbate and Dr. Van Tassell have served as consultants to Swedish Orphan Biovitrum LLC in the past. Dr. Abbate has also served as a consultant to Cardiol Therapeutics, Kiniksa Pharmaceuticals, Implicit Biosciences, Novo Nordisk, Olatec, and R-Pharm. The remaining authors have no disclosures to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Rheumatoid arthritis (RA) is an idiopathic, autoimmune connective tissue disorder that primarily affects the synovial joints, causing symmetric, erosive-deforming polyarthritis. It is also associated with extra-articular manifestations, particularly cardiovascular (CV) diseases (CVD). CV risk modification in RA remains unsolved despite recent advances in the management of RA. RA is an independent risk factor for atherosclerosis. RA and atherosclerosis share similar pathophysiological features (such as the pro-inflammatory cascade activation including interleukin-6) and risk factors (such as microflora dysbacteriosis and smoking). Patients with RA experience an exacerbation of atherogenesis, with atheromas destabilization, endothelial dysfunction, vasculitis, and hypercytokinemia. Consequently, the inflammatory response associated with RA is the basis for CVD development. The treat-to-target strategy not only improved RA control but also had a favorable effect on the morpho-functional state of the CV system in patients living with RA. Thus, disease-modifying antirheumatic drugs (DMARDs) - in particular methotrexate - may have a beneficial effect on the prevention of CV events in RA. It must be mentioned that RA is a serious multi-system disease, not only because of a window period during which the course of RA can be reversed, but also due to early damage to the heart and blood vessels. For this reason, a thorough cardiological assessment must be performed for all patients with RA, regardless of sex, age, disease stage, and disease activity score., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Aims: Trehalose, spermidine, nicotinamide, and polyphenols are natural substances that exert pro-autophagic and antioxidant properties. Their role in blood pressure (BP) regulation and preservation of vascular function in essential hypertension is unknown. The aim of this study was to evaluate the effect of a mixture of these agents on BP level, markers of oxidative stress, autophagy, endothelial function, and vascular stiffness in outpatients with grade 1 uncomplicated essential hypertension., Methods and Results: A single-centre, open-label, case-control, pilot study was conducted in adult outpatients (aged ≥18 years) receiving or not the mixture for two months along with the standard therapies. Both at baseline and at the end of the treatment the following clinical parameters were evaluated: brachial seated office BP level, central aortic pressure, pulse wave velocity, augmentation index (AI@75). Both at baseline and at the end of the treatment, a blood sample was drawn for the measurement of: H 2 O 2 , HBA%, levels of sNOX2-dp, Atg 5, P62, endothelin 1, and NO bioavailability. The mixture of nutraceuticals did not influence BP levels. Patients receiving the mixture showed a significant decrease of oxidative stress, stimulation of autophagy, increased NO bioavailability and no increase of the AI@75, in contrast to what observed in hypertensive patients not receiving the mixture., Conclusions: The supplementation of the trehalose, spermidine, nicotinamide, and polyphenols mixture counteracted hypertension-related arterial stiffness through mechanisms likely dependent on oxidative stress downregulation and autophagy stimulation. These natural activators of autophagy may represent favourable adjuvants for prevention of the hypertensive cardiovascular damage., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Sepsis is caused by dysregulated immune responses due to infection and still presents high mortality rate and limited efficacious therapies, apart from antibiotics. Recent evidence suggests that very high dose proton pump inhibitors might regulate major sepsis mediators' secretion by monocytes, which might attenuate excessive host reactions and improve clinical outcomes. This effect is obtained with doses which are approximately 50 times higher than prophylactic esomeprazole single daily administration and 17 times higher than the cumulative dose of a three day prophylaxis. We aim to perform a randomized trial to investigate if high dose esomeprazole reduces organ dysfunction in patients with sepsis or septic shock., Methods: This study, called PPI-SEPSIS, is a multicenter, randomized, double blind, placebo-controlled clinical trial on critically ill septic patients admitted to the emergency department or intensive care unit. A total of 300 patients will be randomized to receive high dose esomeprazole (80 mg bolus followed by 12 mg/h for 72 h and a second 80 mg bolus 12 h after the first one) or equivolume placebo (sodium chloride 0.9%), with 1:1 allocation. The primary endpoint of the study will be mean daily Sequential Organ Failure Assessment (SOFA) score over 10 days. Secondary outcomes will include antibiotic-free days, single organ failure severity, intensive care unit-free days at day 28, and mortality., Discussion: This trial aims to test the efficacy of high dose esomeprazole to reduce acute organ dysfunction in patients with septic shock., Trial Registration: This trial was registered on ClinicalTrials.gov with the trial identification NCT03452865 in March 2018., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

ST-segment elevation myocardial infarction (STEMI) remains a significant source of morbidity and mortality worldwide. Despite advances in treatment leading to a significant reduction in the early complications and in-hospital mortality, a significant proportion of STEMI survivors develop heart failure (HF) at follow-up. The classic paradigm of HF after STEMI is one characterized by left ventricular adverse remodeling (LVAR) and encompasses the process of regional and global structural and functional changes that occur in the heart as a consequence of loss of viable myocardium, increased wall stress and neurohormonal activation, and results in HF with reduced ejection fraction (HFrEF). More recently, however, with further improvements in the treatment of STEMI the incidence and entity of LVAR appear to be largely reduced, yet the risk for HF following STEMI is not abolished and remains substantial, identifying a new paradigm by which patients with STEMI present with HF and preserved EF (HFpEF) characterized by reduction of diastolic or systolic reserve independent of LVAR., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Dyslipidemia is associated with increased cancer risk. However, the prognostic value of visit-to-visit lipid variability (VVLV) is unexplored in this regard. To investigate the associations between the VVLV and the risk of incident cancer, we conducted a retrospective cohort study on adult patients attending a family medicine clinic in Hong Kong during 2000-2003, excluding those with <3 tests for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and total cholesterol (TC) each, those with prior cancer diagnosis, and those with <1 year of follow-up. Visit-to-visit LDL-C, HDL-C, TC, and triglycerides variabilities were measured by the coefficient of variation (CV). Patients were followed up until 31st December 2019 for the primary outcome of incident cancer. Altogether, 69,186 patients were included (26,679 males (38.6%); mean age 60 ± 13 years; mean follow-up 16 ± 3 years); 7958 patients (11.5%) had incident cancer. Higher variability of LDL-C, HDL-C, TC, and TG was associated with higher risk of incident cancer. Patients in the third tercile of the CV of LDL-C (adjusted hazard ratio (aHR) against first tercile 1.06 [1.00, 1.12], P = 0.049), HDL-C (aHR 1.37 [1.29, 1.44], P< 0.001), TC (aHR 1.10 [1.04, 1.17], P = 0.001), and TG (aHR 1.11 [1.06, 1.18], P < 0.001) had the highest risks of incident cancer. Among these, only HDL-C variability remained associated with the risk of incident cancer in users of statins/fibrates. To conclude, higher VVLV was associated with significantly higher long-term risks of incident cancer. VVLV may be a clinically useful tool for cancer risk stratification., Competing Interests: Conflicts of interest Giuseppe Biondi-Zoccai has consulted for Cardionovum, CrannMedical, Innovheart, Meditrial, Opsens Medical, Replycare, and Terumo. All other authors report no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: there is limited data on Emergency department (ED) cardiovascular disease (CVD) presentations and outcomes amongst cancer patients., Objectives: The present study aimed to describe the clinical characteristics, prevalence, and clinical outcomes of the most common cardiovascular ED admissions in patients with cancer., Methods: All ED encounters with a primary CVD diagnosis from the US Nationwide Emergency Department Sample between January 2016 to December 2018 were stratified by cancer type as well as metastatic status. Multivariable logistic regression was performed to determine the adjusted odds ratios of in-hospital mortality in different groups., Results: From a total of 20,737,247 ED encounters with a primary CVD diagnosis, cancer was present in 3.4%. In patients with cancer the most common CVDs were DVT/PE (20%), hypertensive heart or kidney disease (14.7%), and AF/flutter (11.2%). The distribution of CVDs varied by cancer type, with AF/flutter most common in patients with lung cancer, AMI most common in patients with prostate cancer, heart failure most common in those with haematological malignancies, and patients with colorectal cancer having the greatest frequency of DVT/PE. Cancer status was independently associated with significantly higher risk of mortality in almost all CVD categories, consistent across all the cancer types, amongst which lung cancer patients had the highest risk of mortality across all CVD categories, except intracranial haemorrhage and hypertensive crisis., Conclusions: Cardiovascular presentations to the ED varied by cancer subtype. Across all cancer subtypes, patients presenting with cardiovascular presentations carried a significantly increased risk of mortality compared to patients with no cancer., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The aim was to determine the impact of diabetes mellitus (DM) on outcomes after percutaneous coronary intervention (PCI). There is limited data on the impact of DM and its subtypes among patients who underwent PCI during hospitalization., Methods: All PCI hospitalizations from the National Inpatient Sample (October 2015-December 2018) were stratified by the presence and subtype of DM. Multivariable logistic regression was performed to determine the adjusted odds ratios (aOR) of in-hospital adverse outcomes in type 1 DM (T1DM) and type 2 DM (T2DM) compared to no-DM., Results: Out of 1,363,800 individuals undergoing PCI, 12,640 (0.9%) had T1DM and 539,690 (39.6%) had T2DM. T1DM patients had increased aOR of major adverse cardiovascular and cerebrovascular events (MACCE) (1.26, 95%CI 1.17-1.35), mortality (1.56, 95%CI 1.41-1.72), major bleeding (1.63, 95%CI 1.45-1.84), and stroke (1.75, 95%CI 1.51-2.02), while T2DM patients had only increased aOR of MACCE (1.02, 95%CI 1.01-1.04), mortality (1.10, 95%CI 1.08-1.13) and stroke (1.22, 95%CI 1.18-1.27), compared to no-DM patients. However, both T1DM and T2DM had lower aOR of cardiac complications (0.87, 95%CI 0.77-0.97 and 0.87, 95%CI 0.85-0.89, respectively), in comparison to no-DM patients. When accounting for the indication, both DM subgroups had higher aOR of MACCE, mortality, and stroke compared to no-DM patients in the acute coronary syndrome setting (p < 0.001, for all), while only increased aOR of stroke (1.59, 95%CI 1.17-2.15 for T1DM and 1.12, 95%CI 1.05-1.20 for T2DM) persisted in the elective setting., Conclusions: Patients with DM who have undergone PCI during hospitalization are more likely to experience adverse in-hospital outcomes, and T1DM patients are a particularly high-risk cohort., Competing Interests: Declaration of competing interest 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: We aimed at appraising features and outcomes of patients undergoing MitraClip treatment according to their age., Methods: We queried the prospective GIse registry Of Transcatheter treatment of mitral valve regurgitaTiOn (GIOTTO) multicenter registry dataset including 19 Italian centers performing MitraClip implantation, distinguishing patients <80 vs ≥80 years of age., Results: In total, 1853 patients were included, 751 (40.5%) octogenarians and 1102 (59.5%) non-octogenarians. Several baseline and procedural features were significantly different, including gender, regurgitation etiology, and functional class (all p < 0.05). In-hospital outcomes were similarly satisfactory, with death occurring in 18 (2.4%) and 32 (2.9%, p = 0.561), respectively, and improvement in mitral regurgitation in 732 (97.4%) and 1078 (97.8%, p = 0.746), respectively. After a mean follow-up of 15 months, death occurred in 152 (20.2%) and 264 (24.0%), and cardiac death in 85 (11.3%) and 138 (12.5%), respectively (both p > 0.05). Rehospitalization for heart failure and the composite of cardiac death or rehospitalization for heart failure were significantly less common in octogenarians: 63 (8.4%) vs 156 (14.2%, p < 0.001), and 125 (16.6%) vs 242 (22.0%, p = 0.005), respectively. Multivariable analysis showed that these differences were largely due to confounding features, as after adjustment for baseline, clinical and imaging characteristics no significant difference was found for the above clinical endpoints., Conclusions: Transcatheter mitral valve repair with the MitraClip in carefully selected octogenarians appears feasible and safe, and is associated with favorable clinical outcomes at mid-term follow-up., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: Despite the relation between autoimmune diseases and increased atherosclerotic risk is established, the influence of autoimmune disorders on in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) is only partly known. ISR is an aberrant reparative process mainly characterized by an increased number of vascular smooth muscle cells and excessive deposition of extracellular proteoglycans and type III collagen. Chronic inflammation, always present in autoimmune diseases, modulates the endothelial response to PCI. Aim of this review is to resume the current evidence on the association between ISR and autoimmune diseases, focusing on pathogenic mechanisms and therapeutic targets., Methods: We conducted a comprehensive review of the literature on the relationship between ISR and insulin-dependent diabetes mellitus (IDDM), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid-antibodies syndrome (APS), inflammatory bowel diseases (IBD), and Hashimoto's thyroiditis (HT)., Results: Patients affected with IDDM, RA, SLE, APS, IBD and HT proved to face higher rates of ISR compared to the general population. The endothelial dysfunction seems the principal common pathogenic pathway for ISR and is attributed to both the immune system disorder and the systemic inflammation. Some evidence suggested that methotrexate and anti-tumor necrosis factor treatments can be effective in reducing ISR, while antibodies against vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 showed to reduce neointimal hyperplasia in animal models., Conclusions: Autoimmune diseases are a risk factor for ISR. The study of the potential cardiovascular benefits of the current therapies, mainly anti-inflammatory drugs, and the pursuit of innovative treatments appear of paramount interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Meropenem is a β-lactam, carbapenem antibacterial agent with antimicrobial activity against gram-negative, gram-positive and anaerobic micro-organisms and is important in the empirical treatment of serious infections in Intensive Care Unit (ICU) patients. Multi-drug resistant gram-negative organisms, coupled with scarcity of new antibiotic classes, forced healthcare community to optimize the therapeutic potential of available antibiotics. Our aim is to investigate the effect of continuous infusion of meropenem against bolus administration, as indicated by a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens in a population of ICU patients., Design: Double blind, double dummy, multicenter randomized controlled trial (1:1 allocation ratio)., Setting: Tertiary and University hospitals., Interventions: 600 ICU patients with sepsis or septic shock, needing by clinical judgment antibiotic therapy with meropenem, will be randomized to receive a continuous infusion of meropenem 3 g/24 h or an equal dose divided into three daily boluses (i.e. 1g q8h)., Measurements: The primary endpoint will be a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens. Secondary endpoints will be death from any cause at day 90, antibiotic-free days at day 28, ICU-free days at day 28, cumulative SOFA-free (Sequential Organ Failure Assessment) score from randomization to day 28 and the two, separate, components of the primary endpoint. We expect a primary outcome reduction from 52 to 40% in the continuous infusion group., Conclusions: The trial will provide evidence for choosing intermittent or continuous infusion of meropenem for critically ill patients with multi-drug resistant gram-negative infections., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19) has caused an unprecedented change in the apparent epidemiology of acute coronary syndromes (ACS). However, the interplay between this disease, changes in pollution, climate, and aversion to activation of emergency medical services represents a challenging conundrum. We aimed at appraising the impact of COVID-19, weather, and environment features on the occurrence of ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) in a large Italian region and metropolitan area., Methods and Results: Italy was hit early on by COVID-19, such that state of emergency was declared on January 31, 2020, and national lockdown implemented on March 9, 2020, mainly because the accrual of cases in Northern Italy. In order to appraise the independent contribution on changes in STEMI and NSTEMI daily rates of COVID-19, climate and pollution, we collected data on these clinical events from tertiary care cardiovascular centers in the Lazio region and Rome metropolitan area. Multilevel Poisson modeling was used to appraise unadjusted and adjusted effect estimates for the daily incidence of STEMI and NSTEMI cases. The sample included 1448 STEMI and 2040 NSTEMI, with a total of 2882 PCI spanning 6 months. Significant reductions in STEMI and NSTEMI were evident already in early February 2020 (all p<0.05), concomitantly with COVID-19 spread and institution of national countermeasures. Changes in STEMI and NSTEMI were inversely associated with daily COVID-19 tests, cases, and/or death (p<0.05). In addition, STEMI and NSTEMI incidences were associated with daily NO2, PM10, and O3 concentrations, as well as temperature (p<0.05). Multi-stage and multiply adjusted models highlighted that reductions in STEMI were significantly associated with COVID-19 data (p<0.001), whereas changes in NSTEMI were significantly associated with both NO2 and COVID-19 data (both p<0.001)., Conclusions: Reductions in STEMI and NSTEMI in the COVID-19 pandemic may depend on different concomitant epidemiologic and pathophysiologic mechanisms. In particular, recent changes in STEMI may depend on COVID-19 scare, leading to excess all-cause mortality, or effective reduced incidence, whereas reductions in NSTEMI may also be due to beneficial reductions in NO2 emissions in the lockdown phase., Competing Interests: Declaration of Competing Interest Prof. Biondi-Zoccai has consulted for Cardionovum, Bonn, Germany, InnovHeart, Milan, Italy, Meditrial, Rome, Italy, and Replycare, Rome, Italy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In the era of evidence-based medicine, systematic reviews and meta-analyses are considered at the top of evidence hierarchy. Despite the almost exponential increase in the number of published meta-analyses over the course of the last decades, only a small minority of them are of high quality, with major flaws involving every aspect of the meta-analytic process. The strength of a meta-analysis is closely linked to the quality of the included studies. Once preliminary phases are completed, it is vital that selected papers undergo a thorough quality assessment, using the most appropriate tools among those available. Analytical approaches must be tailored to the nature of the extracted data and the specific purpose of the meta-analysis. Appraisal of heterogeneity is a key step to inform subgroup or meta-regression analyses. The solidity of the results of the main analysis (especially in meta-analyses of observational studies or studies with high heterogeneity) should be tested by means of pertinent sensitivity analyses. Finally, the investigators should be aware of the possibility of publication bias and make efforts to assess it using qualitative and quantitative methods. The aim of the second part of this expert review is to provide guidance on how to appropriately perform trial level meta-analyses, with particular focus on the quality assessment of the included studies, the choice of the appropriate statistical approach, the methods to deal with heterogeneity (including subgroup, meta-regression, and sensitivity analyses), and the appraisal of publication bias., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The number of cardiac surgical meta-analyses and systematic reviews published in the last decades has constantly increased, paralleling the exponential growth observed in virtually all other medical fields. Meta-analyses are open to methodological flaws, however, if best practices are not strictly followed. Assessment of the appropriateness of the research question is a crucial first step. Once a protocol has been developed, this should be registered before the work is initiated. The cornerstone of any systematic review or meta-analysis is a rigorous, comprehensive, and most of all reproducible, search that follows a prespecified and clear strategy. Eligibility criteria must be discussed and agreed upon in advance to guide final study selection, which ultimately lays the foundation for subsequent data extraction. In case of missing or partially reported data, the authors of the original papers should be contacted. Adherence to rigorous methodological rules at each of these stages will warrant availability of good quality data for formal statistical analyses. The aim of the first part of this expert review is to discuss the limits and pitfalls of the meta-analytic approach and provide guidance on how to perform trial-level meta-analyses, with particular reference to the identification of an appropriate research question, the definition and registration of the protocol, the search strategy, the study selection, and the data abstraction., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Contradictory findings from randomized trials addressing similar research questions are not uncommon in medicine. Although differing results may reflect true differences in the treatment effects or in the deliverability of the intervention, more commonly it is as a consequence of small but important discrepancies in study design., Methods: The writing group selected 4 recent trials with apparently contradictory results (2 on revascularization for left main coronary stenosis and 2 on treatment of secondary mitral regurgitation). Detailed methodologic analysis was performed to elucidate the difference in findings., Results: Differences in the definition of the primary outcome are the most likely explanation for the contradictory findings of NOBLE versus EXCEL. Differences in study design (leading to substantially different patient populations) and in outcome definition might explain the discrepant findings of MITRA-FR versus COAPT., Conclusions: As shown by the comparative analysis of NOBLE and EXCEL and MITRA-FR and COAPT, changes in study design, outcome definitions, and patient population can markedly affect the outcome of randomized clinical trials., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The T2238C variant of the atrial natriuretic peptide (ANP) gene has emerged as a novel risk factor for the incidence of cardiovascular events. However, the impact of this variant on cardiovascular outcome in patients with atrial fibrillation (AF) is unknown., Methods: We included 557 anticoagulated patients with non-valvular AF randomly selected from the prospective ATHERO-AF cohort. Patients underwent genetic analysis for the T2238C/ANP variant and were grouped as wild type or heterozygous or homozygous for C2238 variant allele. Primary endpoint was a composite of cardiovascular events (CVEs) including cardiovascular death, fatal/non-fatal ischemic stroke and myocardial infarction. Overall, 429 patients carried the TT wild type genotype, 110 patients (19.7%) were heterozygous (T/C) and 18 patients (3.2%) were homozygous (CC)., Results: Incidence of CVEs was higher in homozygous patients for C2238 allele at unadjusted analysis (log-rank test, p = 0.042 for additive model, p = 0.043 for recessive model). The multivariable Cox proportional hazards regression analysis confirmed that C2238 ANP allele was associated with CVEs in the additive (p = 0.008) and recessive models (p = 0.005)., Conclusions: Carrier status for the C2238/ANP variant allele is associated with an increased risk of CVEs in anticoagulated AF patients., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Transcatheter aortic valve implantation (TAVI) is a safe and beneficial treatment for patients with severe symptomatic aortic stenosis at high and intermediate surgical risk. The safety of the procedure continues to improve thanks to more refined procedural approaches and devices but, also and above all, to the accrual of the procedural knowledge and expertise by the operators. The diversification of the approaches and the possibility to tailor the treatment on the individual needs and anatomical features of the patients allows a rapid learning curve in the management of even complications. Indeed, there are several approaches with which TAVI can be carried out: transfemoral arterial, subclavian, transcarotid, transaortic, transaxillary, transapical, and through right anterior thoracotomy. Although transfemoral venous TAVI is less common, it has already have been carried out using caval-aortic punctures. This field is rapidly evolving, and it will be of paramount importance for interventional cardiologists and cardiothoracic surgeons to keep up to date with further developments. This review intends to give an in-depth and update overview of both conventional and innovative TAVI approaches, with the scope to highlight the relevant advantages, major disadvantages, safety aspects and techniques., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Fractional flow reserve (FFR) provides an objective measurement of the severity of ischemia caused by coronary stenoses in downstream myocardial regions. Data from the interventional cardiology realm have suggested benefits of a FFR-guided percutaneous coronary intervention (PCI) strategy. Limited evidence is available on the use of FFR to guide coronary artery bypass grafting (CABG). The most recent data have shown that FFR might simplify CABG procedures and optimize patency of arterial grafts without any clear impact on clinical outcomes. The aim of this review was to summarize the available data on FFR-based CABG and discuss the rationale and potential consequences of a switch toward FFR-based surgical revascularization strategy., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The optional periprocedural antithrombotic management for carotid artery stenting (CAS) is still debated., Methods: We aimed to compare the procedural and 1-month outlook of patients undergoing CAS with tirofiban as parenteral antiplatelet therapy. We retrospectively compared patients receiving tirofiban during CAS versus those undergoing CAS without tirofiban, using propensity score matching. Ancillary antithrombotic therapy included in all patients aspirin, clopidogrel, and unfractioned heparin. The primary outcome was the change in serum troponin from baseline to postprocedural peak levels. A total of 30 patients undergoing CAS were included, 15 receiving tirofiban on top of heparin and dual oral antiplatelet therapy (DAPT) and 15 receiving only heparin and DAPT. Bail-out use of tirofiban was an exclusion criterion., Results: Baseline troponin was 3.00 (0.06; 5.20) ng/mL in the tirofiban group vs. 4.6 (0.02; 13.10) ng/mL in the no-tirofiban group (P = 0.229), and postprocedural peak 3.5 (0.06; 5.50) ng/mL vs. 6.30 (0.09; 28.40) ng/mL (P = 0.191). Peak-baseline difference in troponin was lower in the tirofiban group than in the no-tirofiban group: 0.3 (0.00; 1.7) ng/mL vs. 1.3 (0.01; 10.00) ng/mL (P = 0.044); the relative peak-baseline change in troponin was analogously different: 24.3% (0%; 44.7%) vs. 50% (21.3%; 80.0%) (P = 0.039). No case of death, myocardial infarction, stroke, or transient ischemic attack occurred during in-hospital stay or at 1-month follow-up., Conclusions: Tirofiban during CAS might provide periprocedural myocardial protection and reduce myocardial injury as determined by serial troponin measurements., (Copyright © 2019. Published by Elsevier Inc.)

Background: Significant aortic stenosis can be effectively treated with transcatheter aortic valve implantation (TAVI) in patients at high or intermediate surgical risk. Predilation is often performed to facilitate TAVI implantation, but its risk-benefit balance with new-generation devices is detabed. We aimed to appraise whether predilation is still needed with new-generation devices for TAVI., Methods/materials: We queried the prospective multicenter RISPEVA (Registro Italiano GISE sull'impianto di Valvola Aortica Percutanea) Study, comparing patients with vs without predilation receiving Acurate, Evolut, Lotus, Portico, or Sapien3. Baseline, procedural features and early clinical and echocardiographic results were compared with unadjusted and adjusted analyses., Results: A total of 1409 subjects were included, 1055 (74.9%) receiving predilation, and 354 (25.1%) undergoing direct TAVI. Several baseline and procedural differences were evident at unadjusted analysis between the two groups, including device success, procedural success, contrast volume, procedural time, mean post-procedural gradient, and prevalence of aortic regurgitation 2+ (all p < 0.05). Adjusted analysis showed that only procedural time remained significantly impacted by predilation (average reduction in procedural time with predilation of -12.9 [95% confidence interval -21.0; -4.8] minutes, p = 0.002). Subgroup unadjusted and adjusted analysis showed that predilation was associated with shorter procedural times only when Evolut or Portico devices were used (all p < 0.05). Clinical and echocardiographic follow-up up to 1 month showed similar results irrespective of predilation at both unadjusted and adjusted analysis., Conclusion: TAVI without predilation is not associated with adverse procedural, clinical or echocardiographic results when new-generation devices are used. Predilation may however reduce procedural time with Evolut and Portico devices., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The impact of seasonal changes on the incidence of acute myocardial infarction has been incompletely appraised, especially in the modern era of primary percutaneous coronary intervention (PPCI). We aimed to appraise the overall and season-specific impact of climate changes on the daily rate of PCCI., Methods: Details on PPCI and climate changes were retrospectively collected in three high-volume Italian institutions with different geographical features. The association between rate of PPCI and temperature, atmospheric pressure (ATM), humidity and rainfall was appraised with Poisson models, with overall analyses and according to season of the year., Results: Details on 6880 days with a total of 4132 PPCI were collected. Overall adjusted analysis showed that higher minimum atmospheric pressure 3 days before PPCI were associated with lower risk (regression coefficient = 0.999 [95% confidence interval 0.998-1.000], p = 0.030). Focusing on season, in Winter PPCI rates were increased by lower same day mean temperature (0.973 [0.956-0.990], p = 0.002) and lower rainfall (0.980 [0.960-1.000], p = 0.049). Conversely, in Spring greater changes in atmospheric pressure 3 days before PPCI were associated with increased risk (1.023 [1.002-1.045], p = 0.032), with similar effects in Summer for minimum temperature on the same day (1.022 [1.001-1.044], p = 0.040)., Conclusions: Climate has a significant impact on the risk of PPCI in the current era, with a complex interplay according to season. Higher risk risk is expected with lower minimum atmospheric pressure in the preceding days, lower rainfall in Winter, greater changes in atmospheric pressure in Spring, and higher temperatures in Summer. These findings have important implications for prevention strategies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Few randomized trials have evaluated the use of non-invasive ventilation (NIV) for early acute respiratory failure (ARF) in non-intensive care unit (ICU) wards. The aim of this study is to test the hypothesis that early NIV for mild-moderate ARF in non-ICU wards can prevent development of severe ARF., Design: Pragmatic, parallel group, randomized, controlled, multicenter trial., Setting: Non-intensive care wards of tertiary centers., Patients: Non-ICU ward patients with mild to moderate ARF without an established indication for NIV., Interventions: Patients will be randomized to receive or not receive NIV in addition to best available care., Measurements and Main Results: We will enroll 520 patients, 260 in each group. The primary endpoint of the study will be the development of severe ARF. Secondary endpoints will be 28-day mortality, length of hospital stay, safety of NIV in non-ICU environments, and a composite endpoint of all in-hospital respiratory complications., Conclusions: This trial will help determine whether the early use of NIV in non-ICU wards can prevent progression from mild-moderate ARF to severe ARF., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Current guidelines recommend intravascular ultrasound (IVUS) or fractional flow reserve (FFR) to decide upon ambiguous left main (LM) disease. However, no study has compared the safety of LM revascularization deferral based on FFR or IVUS., Methods: MEDLINE/PubMed was systematically screened for studies reporting on deferred treatment of angiographically ambiguous LM based upon FFR or IVUS evaluation. Baseline, angiographic and outcome data were appraised and pooled separately for each strategy according to random-effect models with inverse-variance weighting., Results: A total of 908 LM stenoses from 7 FFR and 5 IVUS studies were included with median follow-up of 29.0 and 31.5 months respectively. Per year of follow-up occurrence of overall MACE were 5.1% in FFR group and 6.4% in IVUS group while death, myocardial infarction, LM revascularization were respectively 2.6%, 1.5% and 1.8% vs. 3.0%, 0.5% and 2.2%. Meta-regression analysis suggested the influence of a distal LM stenosis on MACE in FFR group (β = 0.06, p = 0.01) and age in IVUS group (β = 0.4, p = 0.001). In individual studies several independent predictors of MACE were identified including use of lower doses of intracoronary adenosine (OR 1.39, p = 0.04) in FFR group and plaque burden (OR 1.34, p = 0.025), number of other diseased vessels (OR 1.39, p = 0.04) and any untreated stenosis (OR 3.80; p = 0.037) in IVUS- studies., Conclusions: Deferring LM intermediate stenosis on the basis of FFR or IVUS showed an acceptable and similar risk of events in a mid-term follow-up. Conversely, several different variables related to each technique showed an interaction on outcome., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: The risk of recurrence of myocardial infarction (MI) in HIV patients presenting with acute coronary syndrome (ACS) is well known, but there is limited evidence about potential differences in coronary plaques compared to non-HIV patients., Methods: In this multicenter case-control study, HIV patients presenting with ACS, with intravascular-ultrasound (IVUS) data, enrolled between February 2015 and June 2017, and undergoing highly active antiretroviral therapy (HAART), were retrospectively compared to non-HIV patients presenting with ACS, before and after propensity score with matching, randomly selected from included centers. Primary end-point was the prevalence of multivessel disease. Secondary end-points were the prevalence of abnormal features at IVUS, the incidence of major-acute-cardiovascular-events (MACE), a composite end point of cardiovascular death, MI, target lesion revascularization (TLR), stent thrombosis (ST), non-cardiac death and target vessel revascularization (TVR). For each end-point, a subgroup analysis was conducted in HIV patients with CD4 cell count <200/mm 3 ., Results: Before propensity score, 66 HIV patients and 120 non-HIV patients were selected, resulting in 20 and 40 after propensity score. Patients with multivessel disease were 11 and 17, respectively (p = 0.56). IVUS showed a lower plaque burden (71% vs. 75%, p < 0.001) and a higher prevalence of hyperechoic non-calcified plaques (100% vs. 35%, p < 0.05) in HIV patients; a higher prevalence of hypoechoic plaques (7% vs. 0%, p < 0.05), a higher incidence of MACE (17.4% vs. 9.1% vs. l'8.0%, p < 0.05), MI recurrence (17.2% vs. 0.0% vs. 2.3%, p < 0.05), and ST (6.7% vs. 0.3% vs. 03%, p < 0.05) in HIV patients with CD4 < 200/mm 3 ., Conclusions: Our study may provide a part of the pathophysiological basis of the differences in coronary arteries between HIV-positive and HIV-negative patients, suggesting that the former present with peculiar morphological features at IVUS, even after adjustment for clinical variables. Furthermore, we confirmed that an advanced HIV infection is associated with a high risk of non-calcific plaques and with a worse prognosis, including cardiovascular events and ACS recurrence., (Copyright © 2018 Elsevier B.V. All rights reserved.)