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Bruno K Rodiño-Janeiro,1,2 Beatriz Paradela-Dobarro,1 María Isabel Castiñeiras-Landeira,1 Sergio Raposeiras-Roubín,1,3 José R González-Juanatey,1,3,4 Ezequiel Álvarez1,4 1Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain; 2European Molecular Biology Laboratory, Grenoble, France; 3Cardiology Department, University Clinic Hospital of Santiago de Compostela, Santiago de Compostela, Spain; 4Medicine Department, University of Santiago de Compostela, Santiago de Compostela, Spain Abstract: The implications of reactive oxygen species in cardiovascular disease have been known for some decades. Rationally, therapeutic antioxidant strategies combating oxidative stress have been developed, but the results of clinical trials have not been as good as expected. Therefore, to move forward in the design of new therapeutic strategies for cardiovascular disease based on prevention of production of reactive oxygen species, steps must be taken on two fronts, ie, comprehension of reduction-oxidation signaling pathways and the pathophysiologic roles of reactive oxygen species, and development of new, less toxic, and more selective nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors, to clarify both the role of each NADPH oxidase isoform and their utility in clinical practice. In this review, we analyze the value of NADPH oxidase as a therapeutic target for cardiovascular disease and the old and new pharmacologic agents or strategies to prevent NADPH oxidase activity. Some inhibitors and different direct or indirect approaches are available. Regarding direct NADPH oxidase inhibition, the specificity of NADPH oxidase is the focus of current investigations, whereas the chemical structure-activity relationship studies of known inhibitors have provided pharmacophore models with which to search for new molecules. From a general point of view, small-molecule inhibitors are preferred because of their hydrosolubility and oral bioavailability. However, other possibilities are not closed, with peptide inhibitors or monoclonal antibodies against NADPH oxidase isoforms continuing to be under investigation as well as the ongoing search for naturally occurring compounds. Likewise, some different approaches include inhibition of assembly of the NADPH oxidase complex, subcellular translocation, post-transductional modifications, calcium entry/release, electron transfer, and genetic expression. High-throughput screens for any of these activities could provide new inhibitors. All this knowledge and the research presently underway will likely result in development of new drugs for inhibition of NADPH oxidase and application of therapeutic approaches based on their action, for the treatment of cardiovascular disease in the next few years. Keywords: nicotinamide adenine dinucleotide phosphate oxidase, NOX, cardiovascular therapeutic targets, inhibitors, pharmacophore models

Abstract Background Since post-infarction heart failure (HF) determines a great morbidity and mortality, and given the physiopathology implications of advanced glycation end products (AGE) in the genesis of myocardial dysfunction, it was intended to analyze the prognostic value of these molecules in order to predict post-infarction HF development. Methods A prospective clinical study in patients after first acute coronary syndrome was conducted. The follow-up period was consisted in 1 year. In 194 patients consecutively admitted in the coronary unit for myocardial infarct fluorescent AGE levels were measured. The association between glycaemic parameters and the development of post-infarction HF were analyzed in those patients. Finally, we identified the variables with independent predictor value by performing a multivariate analysis of Hazard ratio for Cox regression. Results Eleven out of 194 patients (5.6%) developed HF during follow-up (median: 1.0 years [0.8 - 1.5 years]). Even though basal glucose, fructosamine and glycated haemoglobin were significant predictive factors in the univariate analysis, after being adjusted by confounding variables and AGE they lost their statistical signification. Only AGE (Hazard Ratio 1.016, IC 95%: 1.006-1.026; p Conclusions AGE are an independent marker of post-infarction HF development risk.

Background: Long-term oral anticoagulation is the mainstay therapy for thromboembolic (TE) prevention in patients with atrial fibrillation. However, left atrial appendage occlusion (LAAO) could be a safe alternative to direct oral anticoagulants (DOACs) in patients with a very high TE risk profile., Objective: The purpose of this study was to compare the safety and efficacy of LAAO vs DOACs in patients with atrial fibrillation at very high stroke risk (CHA 2 DS 2 -VASc [congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65-74 years, sex category] score ≥ 5)., Methods: Data from patients with CHA 2 DS 2 -VASc score ≥ 5 were extracted from a prospective multicenter database. To attenuate the imbalance in covariates between groups, propensity score matching was used (covariates: CHA 2 DS 2 -VASc and HAS-BLED [hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs or alcohol] scores), which resulted in a matched population of 277 patients per group. The primary end point was a composite of cardiovascular death, TE events, and clinically relevant bleeding during follow-up., Results: Of 2381 patients, 554 very high risk patients were included in the study (mean age 79 ± 7 years; CHA 2 DS 2 -VASc score 5.8 ± 0.9; HAS-BLED score 3.0 ± 0.9). The mean follow-up duration was 25 ± 11 months. A higher incidence of the composite end point was documented with DOACs compared with LAAO (14.9 events per 100 patient-years in the DOAC group vs 9.4 events per 100 patient-years in the LAAO group; P = .03). The annualized clinically relevant bleeding risk was higher with DOACs (6.3% vs 3.2%; P = .04), while the risk of TE events was not different between groups (4.1% vs 3.2%; P = .63)., Conclusion: In high-risk patients, LAAO had a similar stroke prevention efficacy but a significantly lower risk of clinically relevant bleeding when compared with DOACs. The clinical benefit of LAAO became significant after 18 months of follow-up., Competing Interests: Disclosures Dr Burkhardt is a consultant for Biosense Webster and Stereotaxis. Dr Chierchia has received compensation for teaching purposes and proctoring from Medtronic, Abbott, Biotronik, Boston Scientific, and Acutus Medical. Dr de Asmundis has received research grants on behalf of the center from Biotronik, Medtronic, Abbott, LivaNova, Boston Scientific, AtriCure, Philips, and Acutus Medical and compensation for teaching purposes and proctoring from Medtronic, Abbott, Biotronik, LivaNova, Boston Scientific, AtriCure, Acutus Medical, and Daiichi Sankyo. Dr Di Biase is a consultant for Biosense Webster, Boston Scientific, Stereotaxis, and St. Jude Medical. Dr Di Biase has received speaker honoraria/travel support from Medtronic, Bristol Meyers Squibb, Pfizer, and Biotronik. Dr Natale has received speaker honoraria from Boston Scientific, Biosense Webster, St. Jude Medical, Biotronik, and Medtronic and is a consultant for Biosense Webster, St. Jude Medical, and Janssen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction and Objectives: Only about 1 out of every 3 patients with acute myocardial infarction (AMI) achieve low-density lipoprotein cholesterol (LDL-C) values <55mg/dL in the first year. The present study aims to evaluate the impact of early intensive therapy on lipid control after an AMI., Methods: An independent, prospective, pragmatic, controlled, randomized, open-label, evaluator-blinded clinical trial (PROBE design) will analyze the efficacy and safety of an oral lipid-lowering triple therapy: high-potency statin+bempedoic acid (BA) 180mg+ezetimibe (EZ) 10mg versus current European-based guidelines (high-potency statin±EZ 10mg), in AMI patients. LDL-C will be determined within the first 48hours. Patients with LDL-C ≥ 115mg/dL (without previous statin therapy), ≥ 100mg/dL (with previous low-potency or high-potency statin therapy at submaximal dose), or ≥ 70mg/dL (with previous high-potency statin therapy at high dose) will be randomly assigned 1:1 between 24 and 72hours post-AMI to the BA/EZ combination or to statin±EZ, without BA. The primary endpoint is the proportion of patients reaching LDL-C <55mg/dL at 8 weeks after treatment., Results: The results of this study will provide novel information for post-AMI LDL-C control by evaluating the usefulness of an early intensive lipid-lowering strategy based on triple oral therapy., Conclusions: Early intensive lipid-lowering triple oral therapy vs the treatment recommended by current clinical practice guidelines could facilitate the achievement of optimal LDL-C levels in the first 2 months after AMI (a high-risk period)., Identification Number: EudraCT 2021-006550-31., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Diabetes mellitus (DM) increases the probability of presenting atrial fibrillation (AF) and it is a predictor of its ischemic stroke. There is limited information of the association between glycated hemoglobin (HbA1c) levels and ischemic, embolic or bleeding events in patients with pre-DM and AF., Methods: To investigate whether the presence of pre-DM in patients with AF predicts ischemic or bleeding events, myocardial infarction or mortality, we performed a retrospective study with a final cohort of 2993 non-diabetic patients with AF and data of glycated hemoglobin (HbA1c). We divided the cohort in two groups: those with normal glucose (n = 1351) and those with pre-diabetes (n = 1642). Incidence rates were calculated as the number of events per 100 person-years and were then compared between groups. Competitive hazard regression analysis for non-fatal events(death as the competing event) and conventional Cox regression for mortality were performed., Results: There was not difference between groups for incidence rates of the different events per 100 person-years. Even considering HbA1c as continuous variable, the unadjusted analysis showed no relation between levels of HbA1c and more risk of events. This association remained not significant after adjustment for CHA 2 DS 2 -VASc score, HAS-BLED score and anticoagulation therapy., Conclusion: In this study of 2993 non-diabetic patients with new-onset AF, we have not found an association between HbA1c and worse prognosis when it is in the range of pre-diabetes., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Data on the association between kidney function and Takotsubo syndrome (TTS) outcomes are scarce and conflictive., Objective: To assess the impact of chronic kidney disease (CKD) and acute renal failure (ARF) in patients with TTS., Material and Methods: Patients from the prospective nation-wide (RETAKO) registry were included and divided into quartiles of maximum creatinine (Cr) level during hospitalization., Results: The prevalence of CKD and ARF in the whole RETAKO cohort was 5.4% and 11.7%, respectively. Compared to Q1 (Cr <0.71), patients within Q4 (Cr > 1.1) had lower left ventricular ejection fraction on admission (38.5 ± 12 vs 43.3 ± 11.3, p = 0.002) and higher bleeding rates during hospitalization (6.7% vs 2%, p = 0.005). In addition, compared to Q1, Q4 patients have a greater incidence of cardiogenic shock (17.3% vs 5.6%, p < 0.001), and a higher rate of 5-year all-cause death and major adverse cardiovascular events (31.5% vs 15.8%, p < 0.001 and 22.5% vs 9.3%, p < 0.001, respectively)., Conclusions: TTS patients with CKD have a higher incidence of ARF and exhibit greater Cr on admission, which were linked with higher rates of cardiogenic shock, bleeding during hospitalization as well as major adverse cardiovascular events and all-cause death during a 5-year follow-up., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background : Acute cardiac injury (ACI) after COVID-19 has been linked with unfavorable clinical outcomes, but data on the clinical impact of elevated cardiac troponin on discharge during follow-up are scarce. Our objective is to elucidate the clinical outcome of patients with elevated troponin on discharge after surviving a COVID-19 hospitalization. Methods : We conducted an analysis in the prospective registry HOPE-2 (NCT04778020). Only patients discharged alive were selected for analysis, and all-cause death on follow-up was considered as the primary endpoint. As a secondary endpoint, we established any long-term COVID-19 symptoms. HOPE-2 stopped enrolling patients on 31 December 2021, with 9299 patients hospitalized with COVID-19, of which 1805 were deceased during the acute phase. Finally, 2382 patients alive on discharge underwent propensity score matching by relevant baseline variables in a 1:3 fashion, from 56 centers in 8 countries. Results : Patients with elevated troponin experienced significantly higher all-cause death during follow-up (log-rank = 27.23, p < 0.001), and had a higher chance of experiencing long-term COVID-19 cardiovascular symptoms. Specifically, fatigue and dyspnea (57.7% and 62.8%, with p -values of 0.009 and <0.001, respectively) are among the most common. Conclusions: After surviving the acute phase, patients with elevated troponin on discharge present increased mortality and long-term COVID-19 symptoms over time, which is clinically relevant in follow-up visits.

Background and Aims: Liver diseases play an important role in the development and progression of atrial fibrillation (AF). The Fibrosis-4 (FIB-4) index is a non-invasive score recommended for detecting liver fibrosis. Since the association between liver fibrosis and outcomes of AF patients is still not well defined, we aim to analyze prognosis impact of FIB-4 index in those patients., Methods: A retrospective population-based cohort study was performed with 12,870 unselected patients from a single health area in Spain with AF from 2014 to 2019. Cox regression models were used to estimate the association of FIB-4 index with mortality. The association with ischemic stroke (IS), major bleeding (MB), acute myocardial infarction (AMI), and heart failure (HF) was assessed by competing risk analysis., Results: A total of 61.1%, 22.0%, and 16.9% were classified as low, moderate and high risk of liver fibrosis according to FIB-4 index, respectively. During a mean follow-up of 4.5 ± 1.7 years, FIB-4 index was associated with mortality (adjusted HR 1.04; 95% CI 1.01-1.06; p = 0.002), MB and HF (adjusted sHR 1.03, 95% CI 1.01-1.04; p = 0.004), but not with IS or with AMI. The association between FIB-4 and MB was only found in patients treated with vitamin K antagonists, not in patients on direct oral anticoagulants., Conclusions: The FIB-4 index, a non-invasive scoring method for evaluating liver fibrosis, is independently associated with all-cause mortality, MB and HF in patients with AF, suggesting that it may be useful as a risk assessment tool to identify adverse outcomes in patients with AF., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Takotsubo syndrome (TTS) during the peripartum period is a relevant cause of morbidity in this population; its clinical course and prognosis, compared to the general TTS population, is yet to be elucidated. Our aim was to analyze the clinical features and prognosis of peripartum TTS in a nationwide prospective specifically oriented registry database and consider the published literature. Peripartum TTS patients from the prospective nationwide RETAKO registry-as well as peripartum TTS patients from the published literature-were included, and multiple comparisons between groups were performed in order to assess for statistically and clinically relevant prognostic differences between the groups. Patients with peripartum TTS exhibit a higher prevalence of secondary forms, dyspnea, atypical symptoms, and echocardiographic patterns, as well as less ST-segment elevation than the general TTS population. In the literature, patients with peripartum TTS had a higher Killip status on admission. TTS during the peripartum period has a higher prevalence of angina and dyspnea, as well as physical triggers, neither of which are related to a worse prognosis. Killip status on admission was higher in the literature for patients with TTS but with excellent mid- and long-term prognoses after the acute phase, despite mostly being secondary forms.

Introduction and Objectives: Atrial fibrillation (AF) is linked to heart failure (HF). However, little has been published on the factors that may precipitate the onset of HF in AF patients. We aimed to determine the incidence, predictors, and prognosis of incident HF in older patients with AF with no prior history of HF., Methods: Patients with AF older than 80 years and without prior HF were identified between 2014 and 2018., Results: A total of 5794 patients (mean age, 85.2±3.8 years; 63.2% women) were followed up for 3.7 years. Incident HF, predominantly with preserved left ventricular ejection fraction, developed in 33.3% (incidence rate, 11.5-100 people-year). Multivariate analysis identified 11 clinical risk factors for incident HF, irrespective of HF subtype: significant valvular heart disease (HR, 1.99; 95%CI, 1.73-2.28), reduced baseline left ventricular ejection fraction (HR, 1.92; 95%CI, 1.68-2.19), chronic pulmonary obstructive disease (HR, 1.59; 95%CI, 1.40-1.82), enlarged left atrium (HR 1.47, 95%CI 1.33-1.62), renal dysfunction (HR 1.36, 95%CI 1.24-1.49), malnutrition (HR, 1.33; 95%CI, 1.21-1.46), anemia (HR, 1.30; 95%CI, 1.17-1.44), permanent AF (HR, 1.15; 95%CI, 1.03-1.28), diabetes mellitus (HR, 1.13; 95%CI, 1.01-1.27), age per year (HR, 1.04; 95%CI, 1.02-1.05), and high body mass index for each kg/m 2 (HR, 1.03; 95%CI, 1.02-1.04). The presence of incident HF nearly doubled the mortality risk (HR, 1.67; 95%CI, 1.53-1.81)., Conclusions: The presence of HF in this cohort was relatively frequent and nearly doubled the mortality risk. Eleven risk factors for HF were identified, expanding the scope for primary prevention among elderly patients with AF., (Copyright © 2023. Published by Elsevier España, S.L.U.)

Background: The predictive value of bleeding risk scores for atrial fibrillation in older patients is not as well known. The goal of this study was to evaluate the predictive value of HASBLED, ORBIT and ATRIA for major bleeding (MB) and intracranial hemorrhage (ICH) in patients ≥ 75 years with atrial fibrillation and oral anticoagulation (OAC)., Methods: A retrospective unicenter study including patients ≥ 75 years with atrial fibrillation (AF) and OAC. A total of 7613 patients ≥ 75 years with AF and OAC included between 2014 and 2018 (registry: NCT04364516). We analyzed the discriminative value of HASBLED, ATRIA and ORBIT scores for bleeding endpoints (major bleeding as primary endpoint and intracerebral hemorrhage as secondary). Cox regression was used to predict major bleeding with each scale and also for searching other variables potentially predictor of major bleeding. Model discrimination was assessed using Harrell's C-statistic. Calibration was assessed with goodness-of-fit test proposed by Gronnesby and Borgan., Results: During a mean follow up of 4.0 years (IQR: 2.4-5.7 years), 729 patients developed MB (2.61 per 100 patients/year) and 243 patients developed ICH (0.85 per 100 patients/year). Three scores showed a low discrimination for major bleeding, being ORBIT the best (HASBLED C statistic = 0.557; ATRIA C statistic = 0.568; ORBIT C statistic = 0.595) and also a low discrimination for ICH (HASBLED C statistic = 0.509; ATRIA C statistic = 0.522; ORBIT C statistic = 0.526). Among the variables that are part of the scores and other baseline characteristics, after multivariable adjustment only sex (male), dementia, prior admission for bleeding, anemia and liver disease were found as a predictors of MB., Conclusions: In older patients under oral anticoagulation with atrial fibrillation, the risk scores HASBLED, ATRIA and ORBIT showed a weak discrimination for major bleeding and intracranial hemorrhage. Therefore, other better alternatives should be evaluated for this purpose., Competing Interests: None., (© 2023 JGC All rights reserved; www.jgc301.com.)

Aims: We aimed to explored the association between the use of optimal medical therapy (OMT) in patients with myocardial infarction (AMI) and diabetes mellitus (DM) and clinical outcomes., Methods: Bleeding complications in a Multicenter registry of patients discharged with diagnosis of Acute Coronary Syndrome (BleeMACS) is an international registry that enrolled participants with acute coronary syndrome followed up for at least 1 year across 15 centers from 2003 to 2014. Baseline characteristics and endpoints were analyzed., Results: Among 3095 (23.2%) patients with AMI and DM, 1898 (61.3%) received OMT at hospital discharge. OMT was associated with significantly reduced mortality (4.3% vs. 10.8%, p < 0.001), re-AMI (4.4% vs. 8.1%, p < 0.001), and composite endpoint of death/re-AMI (8.0% vs. 17.6%, p < 0.001). No difference was observed among regions. Propensity score matching confirmed that OMT significantly associated with lower mortality. After adjusting for confounding variables, OMT, drug-eluting stents, and complete revascularization were independent protective factors of 1-year mortality, whereas left ventricular ejection fraction and age were risk factors., Conclusions: Guideline-recommended OMT was prescribed at suboptimal frequencies with geographic variations in this worldwide cohort. OMT can improve long-term clinical outcomes in patients with DM and AMI., Clinical Trial Registration: NCT02466854 June 9, 2015., 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 Elsevier B.V. All rights reserved.)

Background: Medical treatment in Heart Failure (HF) with reduced ejection fraction (HFrEF; LVEF ≤40%) has shifted towards quadruple therapy. Maximum tolerated dose is the goal, yet no hypotension's cut-off point has been specified. In this work, we analyze the impact of intensive drug titration in clinical events, focusing on low blood pressure (BP) patients at hospital discharge., Methods and Results: Retrospective analysis of 713 patients with HFrEF discharged after an acute HF event (mean LVEF 30 ± 5%). Mean SBP was 112.4 ± 16.5 mmHg and 50.6% were discharged on triple therapy. We considered hypotension as a Systolic blood pressure (SBP) <100 mmHg (21.7% of patients, mean SBP was 112.4 ± 16.5 mmHg) and codified the intensity of drug therapy in 5 stages from untreated to very high therapy intensity. The impact of the intensity of treatment was analysed with a propensity score and increasing the intensity was associated in the whole cohort with a reduction of the composite outcome of all-cause mortality and HF readmission, (HR 0.69; CI95% 0.57-0.85, p < 0.001) and benefit in mortality was maintained for SBP < 100 mmHg (HR 0.42; CI95% 0.22-0.82; p = 0.011). Moreover, therapy intensity was clearly associated with lower risk of HF-hospitalization and death after the additional regression, considering SBP as a covariate, in the whole cohort (HR 0.70; CI95% 0.57-0.85; p < 0.001)., Conclusions: In this retrospective cohort analysis, patients with HFrEF and an acute-HF admission, intensive drug dose titration was related to better outcomes, even in patients with low blood pressure at hospital discharge. Therefore, hypotension is not a contraindication for NHB uptitration., 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 Elsevier B.V. All rights reserved.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has revealed several cardiovascular complications, including myocarditis caused by SARS-CoV-2 infection (COVID-19) or after messenger RNA vaccine administration. Because of the high prevalence of COVID-19, the expansion of vaccination programs, and the appearance of new information on myocarditis in these contexts, there is a need to condense the knowledge acquired since the start of the pandemic. To meet this need, this document was drafted by the Myocarditis Working Group of the Heart Failure Association of the Spanish Society of Cardiology, with the collaboration of the Spanish Agency for Medicines and Health Products (AEMPS). The document aims to address the diagnosis and treatment of cases of myocarditis associated with SARS-CoV-2 infection or messenger RNA vaccine administration., (© 2023 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: The impact of cancer on clinical outcomes in patients with atrial fibrillation (AF) is unclear. The aim of this study was to assess how cancer influences the prediction and risk of embolic and hemorrhagic events in patients with AF., Methods: The study population comprised 16 056 patients from a Spanish health area diagnosed with AF between 2014 and 2018. Of these, 1137 (7.1%) had a history of cancer. During a median follow-up of 4.9 years, we assessed the relationship between cancer and bleeding and embolic events by competing risk analysis, considering death as a competing risk., Results: No association was detected between an increased risk of embolic events and cancer overall (sHR, 0.73; 95%CI, 0.41-1.26), active cancer, or any subgroup of cancer. However, cancer was associated with an increased risk of bleeding, although only in patients with active cancer (sHR, 1.42; 95%CI, 1.20-1.67) or prior radiotherapy (sHR, 1.40; 95%CI, 1.19-1.65). Both the CHA 2 DS 2 -VASc and HAS-BLED scores showed suboptimal performance to predict embolic and bleeding risk (c-statistic <0.50), respectively, in nonanticoagulated patients with active cancer. The ratio between the increase in bleeding and the decrease in embolisms with anticoagulation was similar in patients with and without cancer (5.6 vs 7.8; P <.001)., Conclusions: Cancer was not associated with an increased risk of embolic events in AF patients, only with an increased risk of bleeding. However, active cancer worsened the ability of the CHA 2 DS 2 -VASc and HAS-BLED scores to predict embolic and bleeding events, respectively, in nonanticoagulated patients., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Background: No evidence-based therapy has yet been established for Takotsubo syndrome (TTS). Given the putative harmful effects of catecholamines in patients with TTS, beta-blockers may potentially decrease the intensity of the detrimental cardiac effects in those patients., Objective: The purpose of this study was to assess the impact of beta-blocker therapy on long-term mortality and TTS recurrence., Methods: The cohort study used the national Spanish Registry on TakoTsubo Syndrome (RETAKO). A total of 970 TTS post-discharge survivors, without pheochromocytoma, left ventricular outflow tract obstruction, sustained ventricular arrhythmias, and significant bradyarrhythmias, between January 1, 2003, and July 31, 2018, were assessed. Cox regression analysis and inverse probability weighting (IPW) propensity score analysis were used to evaluate the association between beta-blocker therapy and survival free of TTS recurrence., Results: From 970 TTS patients, 582 (60.0%) received beta-blockers. During a mean follow-up of 2.5±3.3 years, there were 87 deaths (3.6 per 100 patients/year) and 29 TTS recurrences (1.2 per 100 patient/year). There was no significant difference in follow-up mortality or TTS recurrence in unadjusted and adjusted Cox analysis (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.59-1.27, and 0.95, 95% CI 0.57-1.13, respectively). After weighting and adjusting by IPW, differences in one-year survival free of TTS recurrence between patients treated and untreated with beta-blockers were not found (average treatment effect -0.01, 95% CI -0.07 to 0.04; p=0.621)., Conclusions: In this observational nationwide study from Spain, there was no significant association between beta-blocker therapy and follow-up survival free of TTS recurrence., (Copyright © 2023. Publicado por Elsevier España, S.L.U.)

Background: Haemoglobin drop is common in acute coronary syndrome (ACS) patients and correlates with poor prognosis. However, the association between mild haemoglobin drop and adverse clinical outcome remains insufficiently investigated. This study aimed to examine the association between in-hospital haemoglobin drop and risk for adverse clinical outcomes in ACS patients, especially those with mild drop., Methods: Included patients from the BleeMACS (Bleeding complications in a Multicenter registry of patients discharged after an Acute Coronary Syndrome) registry were categorized into three groups by the presence and amount of in-hospital haemoglobin drop (non-drop, mild drop and severe drop). The cut-off point between mild drop and severe drop is ≥ 3 g/dL. Multivariate Cox regression was used to assess the association between haemoglobin drop and major adverse cardiac endpoints (MACE). Patients taking potent P2Y 12 inhibitors were selected for the additional analysis. Propensity score matching was used to avoid selective bias in the additional analysis., Results: Of 6911 patients, 4949 patients (71.6%) experienced in-hospital haemoglobin drop. Compare with non-drop group, patients with haemoglobin drop had higher risk of MACE [adjusted hazard ratio (HR) = 1.36, 95% CI: 1.03-1.80 for mild drop group; adjusted HR = 1.70, 95% CI: 1.07-2.68 for severe drop group]. Patients in mild drop group were less likely to receive potent P2Y 12 inhibitors at discharge (mild drop group vs. severe drop group vs. non-drop group: 10.9% vs. 10.7% vs. 23.8%). After propensity score matching adjustment among patients with potent P2Y 12 inhibitors, patients in mild drop group were not associated with an increased risk of MACE than those in non-drop group (adjusted HR = 1.52, 95% CI: 0.49-4.72)., Conclusions: In-hospital haemoglobin drop was common in ACS patients and associated with a higher risk for adverse events. Reduced prescription for potent P2Y 12 inhibitors may be responsible for poor prognoses among patients with mild haemoglobin drop., (© 2022 JGC All rights reserved; www.jgc301.com.)

There is limited knowledge regarding the efficacy and safety of fixed-dose oral anticoagulants in overweight patients because of the possible increased risk of embolism and hemorrhage. This study aimed to evaluate embolic, hemorrhagic, and mortality events in anticoagulated patients, administered both antivitamin K and direct oral anticoagulants based on the body weight (<60 kg, 60 to 100 kg and >100 kg). A retrospective registry-based cohort study including all consecutive patients with a diagnosis of atrial fibrillation between January 2014 and January 2018 in the health area of Vigo (Galicia, Spain) was used (CardioCHUVI-AF registry; ClinicalTrials.gov identifier: NCT04364516). The final cohort comprised 11,821 AF patients. The cohort was classified into 3 categories: low body weight ([LBW], <60 kg, 924 patients); middle body weight (60 to 100 kg, 9,546 patients); and high body weight ([HBW], >100 kg, 958 patients). Outcomes were predicted using the Fine and Gray model and Cox proportional hazards model when appropriate. Middle body weight was the reference group. No association was found between the weight and major bleeding in the univariate analyses: LBW with a sub-distribution hazard ratio (sHR) of 1.13 (95% confidence interval [CI] 0.92 to 1.41), and HBW with an sHR of 1.02 (95% CI 0.83 to 1.26). Stroke/systemic embolism events occurred in 817 patients (6.6%). In the univariate analyses, we found an association between weight and risk of stroke/systemic embolism: LBW sHR 1.37 (95% CI 1.09 to 1.72), and HBW sHR 0.66 (95% CI 0.49 to 0.89) but no association was found in the multivariable model. The same situation was observed with all-cause death: in the univariable model, LBW presented a hazard ratio of 1.48 (95% CI 1.31 to 1.68) and the HBW group presented a hazard ratio of 0.53 (95%CI 0.44 to 0.63) whereas no significant association was found in the multivariable model. We conclude that in our registry, extreme weights were not related to more events during follow-up., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction and Objectives: A paradoxical protective effect of obesity has been previously reported in patients with atrial fibrillation (AF). The aim of this study was to determine the impact of nutritional status and body mass index (BMI) on the prognosis of AF patients., Methods: We conducted a retrospective population-based cohort study of patients with AF from 2014 to 2017 from a single health area in Spain. The CONUT score was used to assess nutritional status. Cox regression models were used to estimate the association of BMI and CONUT score with mortality. The association with embolism and bleeding was assessed by a competing risk analysis., Results: Among 14 849 AF patients, overweight and obesity were observed in 42.6% and 46.0%, respectively, while malnutrition was observed in 34.3%. During a mean follow-up of 4.4 years, 3335 patients died, 984 patients had a stroke or systemic embolism, and 1317 had a major bleeding event. On univariate analysis, BMI was inversely associated with mortality, embolism, and bleeding; however, this association was lost after adjustment by age, sex, comorbidities, and CONUT score (HR for composite endpoint, 0.98; 95%CI, 0.95-1.01; P=.719). Neither obesity nor overweight were predictors of mortality, embolism, and bleeding events. In contrast, nutritional status-assessed by the CONUT score-was associated with mortality, embolism and bleeding after multivariate analysis (HR for composite endpoint, 1.15; 95%CI, 1.14-1.17; P<.001)., Conclusions: BMI was not an independent predictor of events in patients with AF in contrast to nutritional status, which showed a strong association with mortality, embolism, and bleeding. The study was registered at ClinicalTrials.gov (Identifier: NCT04364516)., (Copyright © 2022 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Atrial fibrillation (AF) carries a thrombotic risk related to blood stasis in the left atrium. In patients with rheumatic valve disease and AF, the presence of severe mitral regurgitation (MR) has been shown to reduce the risk of atrial thrombosis and stroke. However, in patients without rheumatic disease, the results are controversial., Aim: To analyse the association between MR and the incidence of stroke in patients with non-rheumatic AF., Methods: We analysed data from the retrospective CardioCHUVI-AF registry, which includes 15,720 patients with AF (without mechanical prostheses or rheumatic valvular disease) in the Vigo area of Spain, during 2014-2018. We grouped the patients according to MR grades: 0-2 (n=15,194) and 3-4 (n=526). We performed univariate and multivariable competitive risk analyses to analyse the association between MR and stroke, with death as the competitive event., Results: During a median (interquartile range [IQR]) follow-up of 4.9 (2.8-4.9) years, 859 patients (5.5%) suffered a stroke. The stroke incidence was 1.3 per 100 person-years (95% confidence interval [95% CI]: 1.2-1.4), with no difference between the MR groups. In univariate analysis, no relationship was observed between MR grade and stroke (subdistribution hazard ratio [sHR]: 1.12, 95% CI: 0.79-1.60; P=0.53); likewise after multivariable analysis (sHR: 0.98, 95% CI: 0.68-1.41; P=0.90). This same relationship was evaluated in subgroups of interest (patients with and without: oral anticoagulation, CHA 2 DS 2 -VASc≥2, prior heart failure, aortic valve disease, left ventricular ejection fraction≤40%, and moderate-severe left atrial dilation), with results consistent with the overall population., Conclusion: In our large registry of patients with non-rheumatic AF, we did not find a protective effect of grade 3-4 MR on the risk of stroke., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Introduction and Objectives: The recent Academic Research Consortium for High Bleeding Risk (ARC-HBR) proposal did not consider acute coronary syndrome (ACS), by consensus, a bleeding criterion per se despite being a high bleeding risk (HBR) scenario. We investigated the applicability of the ARC-HBR classification and criteria in ACS patients., Methods: Patients with ACS undergoing coronary stenting between 2012 and 2018 at a tertiary hospital were retrospectively classified as being at HBR if they met ≥ 1 major or ≥ 2 minor ARC-HBR criteria. The primary endpoint was the 1-year cumulative incidence of Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding., Results: Among 4412 patients, 29.5% were at HBR. The incidence of bleeding was higher in the HBR group than in the non-HBR group (9.4% vs 1.3%; P < .01). The rates of in-hospital periprocedural and postdischarge bleeding were also higher in the HBR group (4.3% vs 0.5% and 5.3% vs 0.9%, respectively; P < .01). Bleeding risk gradually increased with increasing ARC-HBR criteria: 1.8%, 5.0%, 9.4%, 16.8%, 25.2%, and 25.9% for 1 isolated minor criterion, ≥ 2 isolated minor criteria, 1 major criterion (isolated or plus 1 minor criterion), 1 major plus ≥ 2 minor criteria, ≥ 2 major criteria (isolated or plus 1 minor criterion), and ≥ 2 major plus ≥ 2 minor criteria, respectively. Sixteen (80%) out of 20 ARC-HBR criteria satisfied the ARC-HBR predefined cutoffs for BARC 3 or 5 bleeding risk., Conclusions: This study supports the use of the ARC-HBR classification and criteria in the ACS setting. The ARC-HBR classification provides an accurate major bleeding risk estimate and it seems suitable for the identification and management of patients at HBR., (Copyright © 2021 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: Clinical decision-making on anticoagulation in elderly patients with atrial fibrillation (AF) requires clinicians to consider not only the incidence of embolic and bleeding events, but also the risk of death following these adverse events. We aimed to analyze the trade-off between embolic and bleeding events with respect to mortality in elderly patients with AF., Methods: The study cohort comprised all patients aged ≥ 75 years from a Spanish health area diagnosed with AF between 2014 and 2017 (n=9365). The risk of death was investigated using Cox proportional hazards models, including embolic and bleeding events as time-dependent binary indicators., Results: During a median follow-up of 4.0 years, both embolic and bleeding events were associated with a higher risk of death (adjusted HR, 2.39; 95%CI, 2.12-2.69; and adjusted HR, 1.79; 95%CI, 1.64-1.96, respectively). The relative risk of death was 33% higher following an embolism than following a bleeding event (rRR, 1.33; 95%CI, 1.15-1.55), although for transient ischemic attack the risk was lower than for bleeding (rRR, 0.79; 95%CI, 0.63-0.99). The risk of death associated with intracranial hemorrhage was similar to that of major embolisms (RR, 1.00; 95%CI, 0.75-1.29)., Conclusions: In elderly AF patients, embolic events appeared to be associated with a higher risk of mortality than extracranial bleeding, except for transient ischemic attacks, which have a better prognosis. For ICH, the mortality risk was similar to that of major embolism., (Copyright © 2021 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Despite patients with cancer having a higher incidence of atrial fibrillation (AF), little is known about the predictors of outcomes in this population. This study aimed to assess the incidence and predictors of bleeding in patients with AF and cancer. The study population comprised 16,056 patients from a Spanish health area diagnosed with AF between 2014 and 2018 (1,137 with cancer). Competing risk analysis were used to evaluate the association of cancer and bleeding. Discrimination and calibration of bleeding risk scores were assessed by the concordance statistic and the Brier score, respectively. During a median follow-up of 4.9 years, the incidence of bleeding in patients with cancer was 13.2 per 100 patients/year. After multivariate adjustment, a significant association between cancer and bleeding was detected (subdistribution hazard ratio [sHR] 1.18, 95% CI 1.07 to 1.30, p = 0.001), specifically in patients with active cancer or previous radiotherapy. Early age, male gender, diabetes, and anticoagulation were independent predictors of bleeding. However, only anticoagulation with vitamin K antagonist (sHR 1.36, 95% CI 1.03 to 1.78, p = 0.026), not with direct oral anticoagulants (sHR 1.25, 95% CI 0.84 to 1.85, p = 0.270), was associated with bleeding. Discrimination and calibration of Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, and Drugs/alcohol concomitantly (HAS-BLED), AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA), and Hepatic or renal disease, Ethanol abuse, Malignancy, Older (age ≥75 years), Reduced platelet count or function, Rebleeding risk, Hypertension, Anaemia, Genetic factors, Excessive fall risk and Stroke (HEMORR 2 HAGES) scores were poor in patients with cancer (concordance statistic <0.6 and Brier score >0.1). In summary, cancer was associated with an increased risk of bleeding in patients with AF. The predictive ability of bleeding risk scores was poor in this population. Anticoagulation with vitamin K antagonist but not with direct oral anticoagulants, was an independent predictor of bleeding in patients with cancer., Competing Interests: Disclosures Dr. Roubín reports receiving financial support provided by Bayer, Boehringer Ingelheim, Pfizer, and Daichi Sankyo. The remaining authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: Whether Takotsubo syndrome (TTS) should be classified within myocardial infarction with non-obstructive coronary arteries (MINOCAs) is still controversial. The aim of this work was to evaluate the main differences between TTS and non-TTS MINOCAs., Methods and Results: A cohort study based on two prospective registries: TTS from the RETAKO registry ( N :1,015) and patients with non-TTS MINOCAs from contemporary records of acute myocardial infarction from five 5 national centers ( N :1,080). Definitions and management recommended by the ESC were used. Survival analysis was based on the Cox regression analysis; propensity score matching (PS) was created to adjust prognostic variables. Takotsubo syndrome were more often women (85.9 vs. 51.9%; p < 0.001) and older (69.4 ± 12.5 vs. 64.5 ± 14.1 years; p < 0.001). Atrial fibrillation (AF) was more frequent in non-TTS MINOCAs (10.4 vs. 14.4%; p = 0.007). Psychiatric disorders were more prevalent in TTS (15.5 vs. 10.2%, p < 0.001). In-hospital mortality and complications were higher in TTS: 3.4 vs. 1.8%, ( p = 0.015), and 25.8 vs. 11.5%, ( p < 0.001). Global mortality before PS matching was 16.1% in non-TTS MINOCAs and 8.1% in TTS. Median follow-up was 32.4 months; after PS matching, TTS had fewer major adverse cardiovascular events (MACEs): hazard ratio (HR) 0.59; 95% CI 0.42-0.83. There were no differences in global mortality (HR 0.87; CI: 0.64-1.19), but TTS had lower cardiovascular mortality (HR 0.58; CI: 0.35-0.98)., Conclusion: Compared to the rest of MINOCAs, TTS presents a different patient profile and a more aggressive acute phase. However, its long-term cardiovascular prognosis is better. These results support that TTS should be considered a separate entity with unique characteristics and prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer RS-R declared a shared affiliation with one of the authors, IM to the handling editor at time of review., (Copyright © 2022 Lopez-Pais, Izquierdo Coronel, Raposeiras-Roubín, Álvarez Rodriguez, Vedia, Almendro-Delia, Sionis, Martin-Garcia, Uribarri, Blanco, Martín de Miguel, Abu-Assi, Galán Gil, Sestayo Fernández, Espinosa Pascual, Agra-Bermejo, López Otero, García Acuña, Alonso Martín, Gonzalez-Juanatey, Perez de Juan Romero and Núñez-Gil.)

Aims: Despite aortic stenosis (AS) relief, patients undergoing transcatheter aortic valve implantation (TAVI) are at increased risk of developing heart failure (HF) within first months of intervention. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors have been shown to reduce the risk of HF hospitalization in individuals with diabetes mellitus, reduced left ventricular ejection fraction and chronic kidney disease. However, the effect of SGLT-2 inhibitors on outcomes after TAVI is unknown. The Dapagliflozin after Transcatheter Aortic Valve Implantation (DapaTAVI) trial is designed to assess the clinical benefit and safety of the SGLT-2 inhibitor dapagliflozin in patients undergoing TAVI., Methods: DapaTAVI is an independent pragmatic, controlled, prospective, randomized, open-label blinded endpoint, multicentre trial conducted in Spain, evaluating the effect of dapagliflozin 10 mg/day on the risk of death and worsening HF in patients with severe AS undergoing TAVI. Candidate patients should have prior history of HF admission plus ≥1 of the following criteria: (i) diabetes mellitus, (ii) left ventricular ejection fraction ≤40%, or (iii) estimated glomerular filtration rate between 25 and 75 ml/min/1.73 m 2 . A total of 1020 patients will be randomized (1:1) to dapagliflozin vs. no dapagliflozin. Key secondary outcomes include: (i) incidence rate of individual components of the primary outcome; (ii) cardiovascular mortality; (iii) the composite of HF hospitalization or cardiovascular death; and (iv) total number of HF rehospitalizations., Conclusion: DapaTAVI will determine the efficacy and safety of dapagliflozin in a broad spectrum of frail patients after AS relief by TAVI., (© 2021 European Society of Cardiology.)