Acute coronary syndromes (ACS) continue to pose significant challenges for clinical practitioners, particularly regarding the prediction of mid- to long-term outcomes. This study aims to investigate the impact of in-hospital bleeding (IHB) at one-year follow-up in patients admitted for ACS. Data from 23,270 patients enrolled in the international PRAISE registry and discharged after ACS were analyzed. A total of 1,060 patients experienced IHB, while 18,765 did not; 3,445 were excluded due to missing data. The primary endpoint was all-cause mortality at 1 year. Secondary endpoints included major bleeding, reinfarction, and composite endpoints at 1 year. Patients with IHB were older, more frequently female, and had a higher prevalence of cardiovascular risk factors (all p < 0.05). At discharge, IHB patients were less likely to receive optimal medical therapy. At the one-year follow-up, all-cause mortality, major bleeding, and reinfarction were significantly higher in the IHB group (all p < 0.001). Bivariate analysis showed a strong association between IHB and all the outcomes of interest (all OR > 1; all p < 0.001). These associations remained significant even after adjusting for several covariates, except for reinfarction (OR 1.3; 95% CI 0.9–2.11; p = 0.149). Age, female sex, hypertension, and peripheral artery disease were found to be independent predictors of IHB, while DES implantation, radial access and left ventricular ejection fraction were identified as protective factors. IHB is a hallmark of frailty in ACS patients; therefore, greater attention should be given during follow-up to patients experiencing this condition.

BACKGROUNDAcute coronary syndromes (ACS) are a common cause of morbidity and mortality. Several studies have focused on ACS at admission, but limited evidence is available on sex-based comparison of patients discharged after ACS. We appraised the outlook of women and men discharged after ACS.METHODSDetails on women enrolled in the PRAISE registry, an international cohort study spanning 23,700 patients included between 2003 and 2019, were systematically collected. We focused on patient and procedural features, medications at discharge, and 1-year outcomes. The primary endpoint was the composite of death, myocardial infarction, or major bleeding after discharge.RESULTSA total of 17,804 (76.5%) men and 5466 (23.5%) women were included. Several baseline differences were found, including risk factors and prior revascularization (all P<0.05). Men underwent more frequently radial access, and at discharge they received more commonly dual antiplatelet therapy and guideline-directed medical therapy (P<0.001). At 1-year follow-up, risks of death, reinfarction, major bleeding, and non-fatal major bleeding, jointly or individually, were all significantly higher in women (all P≤0.01). All such differences however did not hold true at multivariable analysis, with the exception of major bleeding, which appeared surprisingly less common in females at fully adjusted analysis (P=0.017).CONCLUSIONSWomen, albeit only apparently, had worse outcomes 1 year after discharge for ACS, but adjusted analysis suggested instead that they faced a lower risk of major bleeding after discharge. These findings support the call for more aggressive management of women after ACS.

BACKGROUND:Fast acting insulin analogues are known to improve arterial stiffness. The combination of metformin with insulin represents a widely used therapeutic strategy in diabetes. We hypothesized that insulin treatment in patients with type 2 diabetes (T2D) with long-acting, fast-acting or basal bolus insulin as an add-on to metformin would provide additional improvement of arterial stiffness.METHODS:The INSUlin Regimens and VASCular Functions (INSUVASC) study is a pilot, randomized, open label three-arms study that included 42 patients with type 2 diabetes (T2D) in primary prevention, after a failure to oral antidiabetic agents. Arterial stiffness measurements were performed at fasting and after a standardized breakfast. During the first visit (V1) pre-randomization, participants took only metformin to perform the tests. The same tests were repeated after 4 weeks of insulin treatment during the second visit (V2).RESULTS:Data were available for final analysis in 40 patients, with a mean age of 53.6±9.7 years and a mean duration of diabetes of 10.6±5.6 years. Twenty-one were females (52.5%), hypertension and dyslipidemia were present in 18 (45%) and 17 patients (42.5%), respectively. After insulin treatment, the metabolic control was associated to a decrease in oxidative stress and improvement of endothelial functions, with a post prandial diastole duration increased and a decrease of the peripheral arterial stiffness, with a better post prandial pulse pressure ratio and ejection duration after insulin. In hypertensive patients, insulin treatment provided positive effects by decreasing the pulse wave velocity and improving reflection time.CONCLUSIONS:A short time treatment by insulin in addition to metformin improved myocardial perfusion. Moreover, insulin treatment in hypertensive patients provides a better hemodynamic profile in large arteries.

Ductal patency of preterm infants is potentially associated with long term morbidities related to either pulmonary overflow or systemic steal. When an interventional closure is needed, it can be achieved with either surgical ligation or a catheter-based approach.Transcatheter PDA closure is among the safest of interventional cardiac procedures and it is the first choice for ductal closure in adults, children, and infants weighing more than 6 kg. In preterm and very low birth weight infants, it is increasingly becoming a valid and safe alternative to ligation, especially for the high success rate and the minor invasiveness and side effects. Nevertheless, being it performed at increasingly lower weights and gestational ages, hemodynamic complications are possible events to be foreseen.Procedural steps, timing, results, possible complications and available monitoring systems, as well as future outlooks are here discussed.

Right is right even if no one is doing it; wrong is wrong even if everyone is doing it. Saint Augustine Atherosclerosis is the chronic pathophysiological substrate for coronary artery disease (CAD) and peripheral artery disease (PAD), and its many clinical consequences, which include chronic ischemic syndromes, acute cerebral or cardiac ischemia, as well as sudden cardiac death.1 This condition is characterized by endothelial injury, low-grade inflammation, lipid accumulation, and plaque formation within the intima of the vessel wall.2 The rupture of an atherosclerotic plaque is a predominant cause of acute atherothrombotic events and consequent vessel occlusion, leading to cardiovascular (CV) events, and indeed, CAD and PAD share a common pathophysiology and risk factors (eg, smoking, dyslipidemia, hypertension, and diabetes mellitus).3,4 Clinical guidelines for the management of CAD and PAD have been developed by several societies and organizations. The main goals in these guidelines are to provide symptom relief, to salvage limbs in patients with PAD, and to prevent future CV events. Recommendations for the secondary prevention of CV events include the control of modifiable CV risk factors (eg, diabetes mellitus, hypertension, and smoking) through lifestyle changes and pharmacologic therapy. Moreover, the use of antithrombotics is recommended for most patients.5 Coagulation processes and atherosclerogenesis are closely related by the presence of specific coagulation proteins inside the atherosclerotic lesion, such as tissue factor (TF) and factor VII (FVIII). These factors are expressed on macrophage and vascular smooth muscle cell membrane within the atherosclerotic lesion, and they participate in proatherogenic processes such as inflammation and angiogenesis.6 Moreover, the interaction between these 2 factors constitutes the catalytic complex for thrombin and fibrin synthesis.7 Furthermore, the concomitant presence of proinflammatory molecules (eg, tumor necrosis factor-α [TNF-α], interleukin-1, and interleukin-6 [IL-6]) may enhance this procoagulant condition because anticoagulant proteins such as thrombomodulin and the endothelial cell protein C receptor are downregulated by inflammation.4 In particular, IL-6 is strongly associated with CV events. Thus, increased coagulation activity, possibly due to a chronic inflammatory state, may reduce plaque stability and increase the risk of plaque rupture. Rivaroxaban is an oral, selective direct inhibitor of factor Xa. Numerous clinical trials have analyzed the efficacy and safety of rivaroxaban in the treatment of thromboembolic events, confirming its therapeutic window and predictable anticoagulant effect.8 Moreover, some preclinical evidence on ApoE−/− mice showed that rivaroxaban may induce atherosclerotic lesion stabilization by reducing serum levels of proinflammatory cytokines such as TNF-α and IL-6, in addition to inhibiting the activation of macrophages.9 Furthermore, treatment with rivaroxaban resulted in a significant reduction in levels of biomarkers of coagulation and inflammation in patients with atrial fibrillation (AF) on rivaroxaban therapy in a clinical setting.10 The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial was designed to test the hypothesis that rivaroxaban in combination with aspirin or by itself is more effective than aspirin alone in preventing cardiovascular events in patients with stable atherosclerotic vascular disease.11 In their prospective observational study, Russo et al enrolled patients with an established diagnosis of CAD and/or PAD based on COMPASS study inclusion and exclusion criteria. Eligible patients were treated with aspirin (ASA) 100 mg once daily (OD) and rivaroxaban 2.5 mg twice daily (TD). Although rivaroxaban resulted in a reduction in levels of inflammatory biomarkers in patients with atrial fibrillation (AF), little to no data are available on the anti-inflammatory effects of rivaroxaban 2.5 mg TD and aspirin 100 mg OD in patients with CAD or PAD to date. Russo et al12 showed that in the study population dual pathway inhibition with low dose rivaroxaban and aspirin in patients with established diagnosis of CAD and/or PAD was associated with a reduction in serum levels of some inflammation markers, such as IL-6 and fibrinogen. Moreover, this combined therapy showed little to no impact on hemoglobin values and renal function markers. These findings support the hypothesis of a pleiotropic anti-inflammatory effect of rivaroxaban, in addition to its anticoagulant effect, and partially explain the positive results of COMPASS trial for reduction of cardiovascular events in patients with stable atherosclerotic vascular disease. The association of anticoagulant and antiplatelet drugs at the standard dose has always been contraindicated because it increased bleeding risk without actual benefits for reducing thrombotic risk. Nevertheless, the COMPASS trial put this combination therapy into a new perspective, by adjusting the dose of rivaroxaban and by highlighting its anti-inflammatory properties, fundamental to reduce the procoagulant state. In this issue, Russo et al applied the criteria expressed in the COMPASS trial and partially explained why such dual pathway inhibition holds the promise of the reduction of cardiovascular risk in patients with CAD or PAD. It is then now clear that these preliminary results may suggest a physiopathological rationale for using dual pathway inhibition treatment in patients with myopericardial inflammatory diseases or oxidative stress–based cardiovascular disease, such as atherosclerosis.FIGURE 1.: Pleiotropic anti-inflammatory and anticoagulant effects of rivaroxaban on atherosclerosis. IL = interleukin; TNF = tumor necrosis factor.

The Atrial Flow Regulator (AFR) is a self-expandable double-disk device with a central fenestration, intended to maintain a calibrated communication across the interatrial septum. Only case reports and small case series have been published about its use in the pediatric and congenital heart disease (CHD) population. We described AFR implantation in three congenital patients with different anatomies and indications. In the first case, the AFR was deployed to create a stable fenestration in a Fontan conduit, while in the second, it was used to reduce a Fontan fenestration. In the third case, we implanted an AFR to decompress the left atrium of an adolescent with complex CHD in natural history, with complete mixing, ductal-dependent systemic circulation and combined pulmonary hypertension. This case series demonstrates the great potential of the AFR device in the CHD field, showing versatility, efficacy, and safety in establishing a calibrated and stable shunt, with promising hemodynamic and symptomatic benefits.

BACKGROUND:Despite mounting evidence, the impact of the interplay between weather and pollution features on the risk of acute cardiac and cerebrovascular events has not been entirely appraised. The aim of this study was to perform a comprehensive cluster analysis of weather and pollution features in a large metropolitan area, and their association with acute cardiac and cerebrovascular events.METHODS:Anonymized data on acute myocardial infarction (AMI) and acute cerebrovascular events were obtained from 3 tertiary care centers from a single large metropolitan area. Weather and pollution data were obtained averaging measurements from several city measurement stations managed by the competent regional agency for enviromental protection, and from the Metereological Center of Italian Military Aviation. Unsupervised machine learning was performed with hierarchical clustering to identify specific days with distinct weather and pollution features. Clusters were then compared for rates of acute cardiac and cerebrovascular events with Poisson models.RESULTS:As expected, significant pairwise correlations were found between weather and pollution features. Building upon these correlations, hierarchical clustering, from a total of 1169 days, generated 4 separate clusters: mostly winter days with low temperatures and high ozone concentrations (cluster 1, N.=60, 5.1%), days with moderately high temperatures and low pollutants concentrations (cluster 2, N.=419, 35.8%), mostly summer and spring days with high temperatures and high ozone concentrations (cluster 3, N.=673, 57.6%), and mostly winter days with low temperatures and low ozone concentrations (cluster 4, N.=17, 1.5%). Overall cluster-wise comparisons showed significant differences in adverse cardiac and cerebrovascular events (P<0.001), as well as in cerebrovascular events (P<0.001) and strokes (P=0.001). Between-cluster comparisons showed that cluster 1 was associated with an increased risk of any event, cerebrovascular events, and strokes in comparison to cluster 2, cluster 3 and cluster 4 (all P<0.05), as well as AMI in comparison to cluster 3 (P=0.047). In addition, cluster 2 was associated with a higher risk of strokes in comparison to cluster 4 (P=0.030). Analysis adjusting for season confirmed the increased risk of any event, cerebrovascular events and strokes for cluster 1 and cluster 2.CONCLUSIONS:Unsupervised machine learning can be leveraged to identify specific days with a unique clustering of adverse weather and pollution features which are associated with an increased risk of acute cardiovascular events, especially cerebrovascular events. These findings may improve collective and individual risk prediction and prevention.

Abstract Background Characterization and management of patients with acute coronary syndromes (ACS) remain challenging, and it is unclear whether currently available clinical and procedural features can suffice to inform adequate decision making. Methods Details on patients discharged after an ACS were obtained by querying an extensive multicenter registry, detailing patient features as well as management details. Clinical outcomes included fatal and non-fatal cardiovascular events at 1-year follow-up. After missing data imputation, two unsupervised machine learning approaches (k-means and Clustering Large Applications [CLARA]) were used to generate separate clusters with different features. Bivariate and multivariable-adjusted analyses were performed to compare different clusters for clinical outcomes. Findings: 23,270 patients discharged after ACS were included. Two clusters were identified by k-mean algorithm (k1 and k2), and two clusters by CLARA algorithm (C1 and C2). Differences in 2-years outcomes between k1 and k2 and between C1 and C2 were substantial. K2 cluster (N=21,988) in comparison with k1 cluster (N=1,282) had significantly higher occurrence of death (9.5% vs 3.8%, p<0.001), reinfarction (7.2% vs 3.7%, p<0.001), and major bleeding (6.0% vs 3.0%, p<0.001). Similarly, C1 cluster (N=11,268) showed a worse prognosis than C2 cluster (N=12,002): death (4.8% vs 3.5%, p<0.001), reinfarction (4.5% vs 3.4%, p<0.001), and major bleeding (3.6% vs 2.8%, p=0.001). Most associations did not hold at multivariable analysis based on supervised learning techniques, with the exception of major bleeding (odds ratio=1.37 [95% confidence interval 1.02-1.83] for the k1/C1 subcluster vs k1/C2 subcluster, p=0.039. Conclusions A machine-learning based clustering approach is effective at face value to inform on the prognosis of patients with ACS managed invasively. These findings can be leveraged to inform decision-making in this setting, but also highlight the potential role of cluster analysis in first-in-man, and preapproval studies of medical devices.

This article offers an overview of a four-month research project, conducted in 2019/2020, which studied extremism in the Bosnia and Herzegovina (BiH) football terraces. This work was funded by the International Organisation for Migration - United Nations and by the United States Agency for International Development (USAID). The research focused on risk factors and how these may govern the “entry” of BiH youth into extreme hard-core football fans groups (Ultras1) and prolong their involvement in them. The study highlighted the nature of these groups and their activity providing detailed recommendations for BiH policymakers, security agencies, and football federations and clubs who wish to understand and effectively respond to this emergent threat for public security in BiH.

The survival of pa5ents with single ventricle circula5on undergoing Fontan opera5on has significantly improved in the last decades. However, the neurodevelopmental outcome of this pa5ents is s5ll not sa5sfying and far below the healthy controls. The ae5ology of neurodevelopment disability and mental health disorders is mul5factorial and has a cumula5ve and synergic trend over the years. Gene5c factors, abnormal fetal circula5on, peri and intra-opera5ve care, mul5ple hospitaliza5ons and socioeconomic status play a crucial role in this process. Due to the heterogeneity of anatomies and different treatment possibili5es there is a need for a personalized, mul5disciplinary and transla5onal approach focused on the pa5ent. The introduc5on of new technologies driven by ar5ficial intelligence and the con5nuous integra5on of in vivo data and biomedical simula5ons into medicine promises significant improvements in pathologies diagnosis and treatment thus enhancing the quality of life of pa5ents and their families.

BACKGROUND Despite unanimous calls for more equitable access and support to female researchers, there are persistent barriers to women's career progression and professional fulfillment. These discriminative hurdles undermine female gender in science and have detrimental effects on research activities and female professionals and patients. There is no data on women's outlook in cardiovascular research in Italy, which limits appropriate remedial actions. We aimed at providing an updated perspective on top Italian cardiovascular researchers, focusing on women vs. men comparisons. METHODS Top Italian cardiovascular researchers were retrieved from a dedicated and validated Scopus query. Researchers' sex was assigned according to the given name with a consensus process. Several metrics were compared, including global rank, total cites, total cites adjusted by academic age, h index, and selfcitation percentage. Bivariate and propensity score-adjusted analyses were used for inferential purposes. RESULTS Our analysis shows the existence of a gender gap: the number of scientific articles published by Italian male researchers in their careers is significantly higher than their female counterparts (p=0.002). For men, the year of first publication is earlier (p=0.001); they also published more articles as a single author, or single+first author or single+first+last author. Men's papers cited at least once were more than those of women (p=<0.001), and the total number of citations was significantly higher for men (p=0.002). These results remain significant both in the analysis excluding self-citations as well as in the analysis including self-citations. The single-year analysis (2019) confirms the significance of the career analysis, adding that men have a higher rank based on composite score (p=0.041, or p=0.005 if including self-citation). Finally, men have a higher percentage of self-citation in 2019 than women (p=0.008). CONCLUSIONS The gender disparity is still a limiting factor in Italian cardiovascular research. Despite career advancement, women continue to be underrepresented. Men retain more leadership positions in academia and maintain the edge for scientific work productions. More efforts are needed to ensure equity between men and women.

The art of life is a constant readjustment to our surroundingsKakuzo Okakaura Out-of-hospital cardiac arrest (OHCA) is a leading cause of global mortality, with more than 200,000 people in the USA dying suddenly from it every year, often due to coronary heart disease.1Adrie C. Cariou A. Mourvillier B. et al.Predicting survival with good neurological recovery at hospital admission after successful resuscitation of out-of-hospital cardiac arrest: the OHCA score.Eur Heart J. 2006; 27: 2840-2845Crossref PubMed Scopus (219) Google Scholar Moreover, despite strong advances in cardiac resuscitation techniques, overall prognosis and neurological outcomes seem to be post-OHCA and have not showed a clear improvement in the past 30 years.2Myat A. Song K.J. Rea T. Out-of-hospital cardiac arrest: current concepts.Lancet. 2018; 391: 970-979Summary Full Text Full Text PDF PubMed Scopus (171) Google Scholar In community-wide studies, overall survival rates ranged from 4% to 33%. In particular, the estimated survival to discharge rate, weighted by person-years, was 6.8% in North America, 7.6% in Europe, and 3% in Asia.3Berdowski J. Berg R.A. Tijssen J.G. Koster R.W. Global incidences of out-of-hospital cardiac arrest and survival rates: systematic review of 67 prospective studies.Resuscitation. 2010; 81: 1479-1487Summary Full Text Full Text PDF PubMed Scopus (1173) Google Scholar This variability highlights the need for a thorough investigation of determining factors, thus leading to an improvement in OHCA management and outcomes. Hence the creation of different scores, such as Return of spontaneous circulation After Cardiac Arrest (RACA) and Utstein-Based Return of Spontaneous Circulation (ROSC)(UB-ROSC), designed to identify weak points in the chain of survival and to evaluate the quality of resuscitation strategies and Emergency Medical Services (EMS) systems. In 2011, Gräsner et al. developed a score to predict the probability of ROSC after OHCA, the RACA score.4Gräsner J.T. Meybohm P. Lefering R. et al.ROSC after cardiac arrest–the RACA score to predict outcome after out-of-hospital cardiac arrest.Eur Heart J. 2011; 32: 1649-1656Crossref PubMed Scopus (98) Google Scholar The RACA score was developed with data from the German Resuscitation Registry and incorporates multiple pre-resuscitation variables that have a crucial impact on the probability of ROSC. The RACA score was not designed as a prediction tool to facilitate resuscitation decisions but, by providing a predicted ROSC rate, the score could identify weak points in the chain of survival, serving as a quality indicator of resuscitation strategies and EMS systems. Moreover, since the original study was performed with data from a German registry, its application in other cohorts with different EMS systems and populations led to mixed results.5Kupari P. Skrifvars M. Kuisma M. External validation of the ROSC after cardiac arrest (RACA) score in a physician staffed emergency medical service system.Scand J Trauma Resusc Emerg Med. 2017; 25: 34Crossref PubMed Scopus (17) Google Scholar Recently, Baldi et al. generated the UB-ROSC score to identify the probability of ROSC and survival to hospital admission of patients with OHCA.6Baldi E. Caputo M.L. Savastano S. et al.An utstein-based model score to predict survival to hospital admission: the UB-ROSC score.Int J Cardiol. 2020; 308: 84-89Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar Differently from the RACA score, the UB-ROSC score is able to take into account random effects related to centre, thus making it usable in the field, and possibly supporting resuscitation-related decisions. However, UB-ROSC is a relatively new instrument and has not been widely validated with external patient cohorts, particularly in Asia. For this reason, considering the impactful differences in population characteristics and EMS systems between Asian and European or American cohorts, in this issue of eClinicalMedicine, Nan Liu et al. attempted to develop a Prehospital ROSC (P-ROSC) score suited for patients with OHCA in Asia.7Liu N. Liu M. Chen X. et al.Development and validation of an interpretable prehospital return of spontaneous circulation (P-ROSC) score for patients with out-of-hospital cardiac arrest using machine learning: a retrospective study.eClinicalMedicine. 2022; 48101422Summary Full Text Full Text PDF Scopus (2) Google Scholar To better understand OHCA events in Asian cohorts, the authors queried the PAROS Registry, an international clinical research network founded in 2010. The collected variables ranged from patient-related, event-related, EMS-related, to patient outcomes, thus addressing different parts of the survival chain.8Ong M.E. Shin S.D. De Souza N.N. et al.Outcomes for out-of-hospital cardiac arrests across 7 countries in Asia: the Pan Asian Resuscitation Outcomes Study (PAROS).Resuscitation. 2015; 96: 100-108Summary Full Text Full Text PDF PubMed Scopus (214) Google Scholar At present, the progressive expansion of the use of electronic health records (EHRs) allows the use of the growing quantity and diversity of data to create modern risk models with advanced machine learning solutions.9Xie F. Chakraborty B. Ong M.E.H. Goldstein B.A. Liu N. AutoScore: a machine learning-based automatic clinical score generator and its application to mortality prediction using electronic health records.JMIR Med Inform. 2020; 8: e21798Crossref PubMed Scopus (22) Google Scholar By contrast, although EHRs are indeed rich data sources, numerous data items are collected in a non-systematic way, causing the accumulation of irrelevant and redundant information. Actually, in risk models, more variables do not necessarily lead to better performance.10Sanchez-Pinto L.N. Venable L.R. Fahrenbach J. Churpek M.M. Comparison of variable selection methods for clinical predictive modeling.Int J Med Inform. 2018; 116: 10-17Crossref PubMed Scopus (93) Google Scholar The PAROS Registry has been developed with common taxonomy and a standardised case report form in order to collect and record data in a systematic way, thus making the creation of the risk model effective and precise. In this study, AutoScore, a framework developed to automate the derivation of risk scores using a combination of machine learning and regression modelling, has been used to generate a point-based score, easy to apply to different clinical settings. To check if the P-ROSC score was actually more suitable for Asian populations, RACA score and UB-ROSC score were calculated on the same cohort, using the original formulas developed by the creators, respectively Gräsner et al. and Baldi et al. In this study, the newly developed P-ROSC score showed itself to be a readily accessible risk prediction tool for ROSC probability estimation (Figure 1). Thanks to this study, an accessible and easy-to-use score was therefore developed for estimating the probability of ROSC. Moreover, four variables out of five are shared with RACA and UB-ROSC scores, but the P-ROSC score shows a better performance in Asian cohorts than the other two scores. In conclusion, differences in populations and cohorts are crucial and should be taken into consideration when developing scores that can help evidence-based clinical practice, especially in critical situation such as OHCA. Regarding this context, P-ROSC was the first score to estimate the ROSC probability of patients with OHCA in Asia effectively, and it showed great discrimination capabilities, thus serving as a potentially helpful tool to aid clinical decision-making. Alberto Testa has drafted the manuscript and approved the final version. Francesco Versaci has revised the manuscript for important critical content, and approved the final version. Giuseppe Biondi-Zoccai has conceived the manuscript, revised it for important critical content, and approved the final version. Giuseppe Biondi-Zoccai has consulted for Cardionovum, Crannmedical, Innovheart, Meditrial, Opsens Medical, Replycare, and Terumo. All other authors report no conflict of interest. None.

A scholarly retraction can be defined as the action of removing a published article from a scholarly journal, to correct erroneous or fraudulent data [ [1] Baskin P.K. Mink J.W. Gross R.A. Correcting honest pervasive errors in the scientific literature: retractions without stigma. Neurology. 2017; 89: 11-13 Crossref PubMed Scopus (2) Google Scholar ]. The issue of retractions involves every field of medical research, yet it was not studied in detail in the cardiovascular (CV) domain to date. The work of Audisio et al. originally and timely gives us a broad overview of retractions in the CV literature, analyzing 459 retractions in CV literature from 1978 to 2020, published in 228 different journals, with key implications for contributors and perusers of CV scientific works (Fig. 1) [ [2] Audisio K. Robinson N.B. Soletti G.J. Cancelli G. Dimagli A. Spadaccio C. Olaria R.P. Chadow D. Rahouma M. Demetres M. Tam D.Y. Benedetto U. Girardi L.N. Kurlansky P. Fremes S.E. Gaudino M. A survey of retractions in the cardiovascular literature. Int. J. Cardiol. 2022; (in press) Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar ]. A survey of retractions in the cardiovascular literatureInternational Journal of CardiologyVol. 349PreviewRetractions of erroneous and fraudulent papers from the biomedical literature continue to be a major concern. The aim of this analysis is to summarize trends of retractions in the cardiovascular literature over the past four decades. Full-Text PDF

When the battle's lost and won William Shakespeare Ischemic heart disease is still the main cause of death in the general population: approximately every 40 seconds, an American suffers from an acute myocardial infarction (MI).1 Indeed, MI typically and most commonly takes place when an epicardial coronary artery gets partially or completely occluded. If the occlusion is not resolved, due to the lack of oxygenation, ischemia may cause myocardial necrosis leading to scarring and contraction dysfunction; the main objective is then to reperfuse cardiomyocytes to reduce irreversible damage and infarct extension. However, paradoxically, the process of reperfusion itself can damage the myocardium in a phenomenon called “ischemia-reperfusion injury” (IRI).2 Under ischemia, cardiomyocytes start anaerobic metabolism due to the hypoxic condition, causing overproduction of lactic acid and accumulation of carbon dioxide (CO2).3 As a result of intracellular acidosis, the sodium (Na+)/potassium (H+) exchanger channel (NHE) is activated, causing an increased flow of Na+ toward the intracellular environment. This increase in Na+ intracellular concentration can trigger the Na+/calcium (Ca+) exchanger channel (NCE) and cause intracellular calcium overload, and consequent contraction dysfunction. By reperfusing the cardiac tissue, cardiomyocytes become reoxygenated. Moreover, the accumulation of cytosolic calcium leads to the activation of numerous calcium-dependent enzymes.2,3 Among the activated enzymes, there is calpain, a protease, which irreversibly cuts the xanthine-dehydrogenase enzyme, transforming it into the xanthine-oxidase isoform. This last enzyme oxidizes hypoxanthine to uric acid using oxygen as a substrate and producing superoxide anion during the reaction, an important source of detrimental oxygen free radicals.4 Furthermore, nitrogen monoxide produced by endothelial cells in response to ischemia combines with the superoxide anion to form the nitroperoxide radical, further contributing to oxidative stress development; moreover, nitrogen monoxide may be directly quenched by the superoxide anion, thus severely impairing nitric oxide-mediated coronary vasorelaxation. Damage to the mitochondrial membrane (caused by calcium-dependent phospholipases), added to the imbalances in the calcium concentration, determines dysfunctions in the electron transport chain, which increase mitochondrial instability.5 As a result, reactive oxygen species production is increased and the creation of mitochondrial permeability transition pores is favored, with the initiation of the intrinsic pathway of apoptosis. On top of this, several other cells such as platelets, neutrophils, and endothelial cells are involved in the process of IRI. Increase the permeability of the endothelium due to inflammation allows an easier extravasation of neutrophils, which not only leads to the production of reactive oxygen species in the ischemic site, but also assists platelets in the development of the no-reflow phenomenon.6 Furthermore, the process of IRI can extend its effects from the time of reperfusion to days after the establishment of perfusion, causing no-reflow, slow-flow, and a low myocardial perfusion grade. Therefore, prevention is the only weapon available to date to fight IRI. The pharmacologic prevention of IRI has been thoroughly studied in the past 30 years, leading to numerous successes in experimental studies, but with poor results in most clinical settings. In this issue of the Journal, Kakavand et al7 provide a comprehensive review focusing on the impact of preprocedural pharmacologic agents in IRI prevention in the setting of primary percutaneous coronary intervention, categorizing them into 5 main groups based on their mechanism of action: (1) drugs that can reduce oxidative stress, (2) drugs that affect cellular metabolism, (3) rheological agents that can reduce the incidence of microvascular obstruction, (4) agents with anti-inflammatory properties, and (5) agents that have mixed mechanisms of action.7 Perusal of this comprehensive analysis is essential toward a complete understanding of IRI because, despite having established the pathogenic role of this process after ischemia treatment, the multifactorial essence being of IRI makes a global approach to the issue mandatory (Fig 1).FIGURE 1.: Multifactorial nature of ischemia-reperfusion injury. Ca, calcium; Cyt, cytochrome; H, hydrogen; mPTP, mitochondrial permeability transition pore; NA, sodium; NO, nitric oxide; O2, oxygen; ROS, reactive oxygen species.Drugs affecting oxidative stress overall showed efficacy in experimental studies, promising results in some small clinical studies, but failed in major clinical trials.8 Among these, antioxidants such as N-acetylcysteine and carnitine overall showed a significant decrease in infarct size, cardiac markers, and levels of free radicals, and an improvement in the left ventricular (LV) ejection fraction (EF). Carperitide, a recombinant form of human alpha atrial natriuretic peptide, significantly reduced infarct size as well. Drugs affecting cellular metabolism showed mixed results: an early glucose-insulin-potassium infusion lowered the rates of cardiac arrest or in-hospital mortality but did not improve 30-day survival; glucagon-like peptide-1 agonists such as liraglutide showed a reduction in infarct size and an improvement in EF; no-reflow medications showed mixed results. Among anti-inflammatory medications, only inclacumab, a human monoclonal antibody against P-selectin, showed efficacy in reducing myocardial damage. Drugs with mixed mechanisms of action were reported to have similarly mixed results according to different trials: based on the STATIN-STEMI trial, the administration of high-dose atorvastatin was associated with better coronary flow and myocardial perfusion, whereas in the REOPERATOR trial, it showed no benefits in reducing infarct size and LV function.9,10 Based on the EARLY-BAMI trial, the administration of intravenous metoprolol reduced the rate of ventricular arrhythmias but did not affect infarct size, whereas according to the METOCARD-CNIC study, it reduced infarct size and improved EF.11,12 Among these drugs, enalaprilat reduced cardiac markers, lowered the rate of ventricular arrhythmias, enhanced LV function, augmented the levels of L- and P-selectin, and improved the thrombolysis in myocardial infarction frame count.13 It is now clear how, despite promising results obtained in experimental studies, clinical trials on the treatment of IRI showed poor outcomes. Most hypotheses that aim to explain this phenomenon focused on the differences between humans and animal models. In particular, the pathophysiology of MI has different patterns in humans compared with the ones in animal models. First, pigs and primates have little collateral circulation, whereas dogs and cats have a developed collateral blood flow. Humans have sufficient collaterals, which help keeping portions of the myocardium viable even after 4–6 hours from the symptom onset; however, in animal studies, the ischemic time has been reported to be between 30 and 120 minutes, and in clinical conditions, it appeared to be more than 180 minutes. This may explain how clinical trials showed less promising results than the experimental ones, since the early administration of the agents showed more beneficial results in glucose-insulin-potassium9 and inclacumab11 trials. Moreover, the drug delivery into cardiomyocytes can be compromised as long as the epicardial artery is occluded during the ischemic event, so that the intracoronary administration of the agents may lead to better concentrations of the drug in the myocardium. Notably, on top of pharmacologic means to modulate the ischemic cascade, other nonpharmacologic approaches have been proposed, such as extracorporeal shockwave myocardial revascularization and bone-marrow-derived autologous stem cell implantation associated with surgical left ventricular restoration, with mixed but encouraging results.14,15 In conclusion, despite the thorough study of IRI pathophysiology in the past 30 years, it seems that the biochemical processes that lead to this phenomenon are not fully known nor completely understood. The different interactions of the pharmacological agents with the organisms made clearer the multifactorial nature of IRI, and hence the need for a multitargeting approach essential to successfully establish an effective therapy for this phenomenon.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has become first-line treatment for severe aortic valve stenosis in patients with moderate, high or prohibitive surgical risk. However, access site complications may occur more frequently in extreme body mass index (BMI) categories. The aim of this study was to describe the features and outcomes of patients undergoing TAVI in a comprehensive Italian prospective clinical registry, focusing on BMI classes.METHODS: A national prospective database was queried for baseline, procedural, and outcome details of patients undergoing TAVI according to established BMI categories: underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2), and obese (BMI≥30 kg/m2). Short- and long-term outcomes, including major adverse events (MAE), i.e. the composite of death, stroke, myocardial infarction, major vascular complication, major bleeding, or renal failure, were appraised with bivariate and multivariable analyses.RESULTS: A total of 3075 subjects were included, 64 (2.1%) were underweight, 1319 (42.9%) were normal weight, 1152 (37.4%) were overweight, and 540 (17.6%) were obese. Several baseline differences were evident, including gender, diabetes mellitus, renal function, chronic obstructive pulmonary disease, surgical scores, and left ventricular ejection fraction (LVEF) (all P<0.05). Several procedural differences were also evident, including percutaneous approach, predilation, prosthesis type and size (all P<0.05), with postprocedural aortic regurgitation >2+ significantly more common in underweight patients (P<0.05). Nonetheless, unadjusted analysis for one-month outcomes showed similar rates for fatal and non-fatal outcomes, including MAE (all P>0.05), with the notable exception of permanent pacemaker implantation, which was more common in higher BMI classes (P=0.010) Unadjusted analysis for long-term events showed an increased rate of death in underweight patients (P=0.024). Multivariable adjusted analysis confirmed the increased risk of permanent pacemaker implantation in obese patients (P=0.015 when comparing obese vs. normal weight subjects), but disproved differences in long-term mortality and other outcomes (P>0.05 for all comparisons).CONCLUSIONS: Irrespective of BMI class, TAVI is associated with favorable outcomes in surgical high-risk risk patients, with the notable exclusion of permanent pacemaker implantation, which is significantly more common in obese subjects.