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Introduction The interaction between anticoagulants and platelet function is complex. Previous publications showed mixed results regarding the role of heparins in platelet aggregation. On the other hand, the direct thrombin inhibitor (DTI) dabigatran might enhance the risk of myocardial infarction in patients with atrial fibrillation, which could be related to increased platelet aggregability. Methods This was a prospective, interventional study of patients with chronic coronary artery disease (CAD) taking low-dose aspirin. The objective of the current study was to compare the effects of dabigatran versus enoxaparin on platelet aggregability. Subjects initially were on orally administered dabigatran for 5 days followed by subcutaneously administered enoxaparin after a 30-day washout period. Platelet function was assessed at baseline and after each intervention by multiple electrode aggregometry (MEA-ASPI) (primary endpoint), serum thromboxane B2 (TXB2), VerifyNow Aspirin™, and coagulation tests (secondary endpoints). Results Compared to baseline MEA-ASPI values, dabigatran increased platelet aggregation while enoxaparin decreased platelet aggregation (+ 5 U ± 24.1 vs − 6 U ± 22.2, respectively, p = 0.012). The TXB2 assay showed the same pattern (+ 2 pg/ml for dabigatran vs − 13 pg/ml for enoxaparin, p = 0.011). None of the additional tests showed significant differences between the groups. Individually, compared to baseline TXB2 results, enoxaparin significantly decreased platelet activation [33 (16.5–95) pg/mL vs 20 (10–52) pg/mL, respectively, p = 0.026], but no significant differences were observed with dabigatran. Conclusions DTI and anti-Xa drugs exert opposite effects on platelet function. A significant decrease in platelet activation through COX1 (also known as prostaglandin G/H synthase 1) was observed with enoxaparin, but no significant differences in platelet function were observed with dabigatran. Trial Registration ClinicalTrials.gov identifier, NCT02389582.

International audience; Background: Risk prediction tools are lacking for patients with stable disease some years after myocardial infarction (MI).Hypothesis: A practical long‐term cardiovascular risk index can be developed.Methods: The long‐Term rIsk, Clinical manaGement and healthcare Resource utilization of stable coronary artery dISease in post‐myocardial infarction patients prospective global registry enrolled patients 1 to 3 years post‐MI (369 centers; 25 countries), all with ≥1 risk factor (age ≥65 years, diabetes mellitus requiring medication, second prior MI, multivessel coronary artery disease, or chronic non‐end‐stage kidney disease [CKD]). Self‐reported health was assessed with EuroQoL‐5 dimensions. Multivariable Poisson regression models were used to determine key predictors of the primary composite outcome (MI, unstable angina with urgent revascularization [UA], stroke, or all‐cause death) over 2 years.Results: The primary outcome occurred in 621 (6.9%) of 9027 eligible patients: death 295 (3.3%), MI 195 (2.2%), UA 103 (1.1%), and stroke 58 (0.6%). All events accrued linearly. In a multivariable model, 11 significant predictors of primary outcome (age ≥65 years, diabetes, second prior MI, CKD, history of major bleed, peripheral arterial disease, heart failure, cardiovascular hospitalization (prior 6 months), medical management (index MI), on diuretic, and poor self‐reported health) were identified and combined into a user‐friendly risk index. Compared with lowest‐risk patients, those in the top 16% had a rate ratio of 6.9 for the primary composite, and 18.7 for all‐cause death (overall c‐statistic; 0.686, and 0.768, respectively). External validation was performed using the Australian Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events registry (c‐statistic; 0.748, and 0.849, respectively).Conclusions: In patients >1‐year post‐MI, recurrent cardiovascular events and deaths accrue linearly. A simple risk index can stratify patients, potentially helping to guide management.

Background Patients with coronary artery disease (CAD) and previous ischemic cerebrovascular events (ICVE, ischemic stroke, or transitory ischemic attack) constitute a high‐risk subgroup for cardiovascular outcomes. High‐density lipoprotein cholesterol (HDL‐C) levels are correlated with cardiovascular events. Lipid transfer to HDL affects structure size and HDL subclass profile. Impairment of this transfer could influence ischemic risk seen in patients with CAD + ICVE. The objective was to evaluate the HDL ability to receive the lipids in patients with CAD with or without ICVE. Methods Patients with CAD + ICVE (n = 60) and patients with CAD only (n = 60) were matched by age, sex, acute coronary syndromes (ACS) event type, and time elapsed between the ACS event and inclusion in the study. Lipid transfer to HDL was evaluated by incubating donor lipid nanoparticles labeled with radioactive unesterified cholesterol (UC) and esterified cholesterol (EC), phospholipid (PL), and triglyceride (TG) with whole plasma. After the chemical precipitation of non‐HDL fractions and nanoparticles, the supernatant was counted for HDL radioactivity. Results CAD + ICVE group presented with impaired lipid transfer to HDL for PL (CAD + ICVE: 21.14 ± 2.7% vs CAD: 21.67 ± 3.1%, P = .03), TG (CAD + ICVE: 4.88 ± 0.97% vs CAD: 5.63 ± 0.92%, P = .002), and UC (CAD + ICVE: 5.55 ± 1.19% vs CAD: 6.16 ± 1.14%, P = .009). Lipid transfer to HDL was similar in both groups for EC. Adjusted models showed similar results. Conclusion Patients with CAD and ICVE have reduced lipid transfer to HDL compared to those with CAD only. Dysfunctional HDL may account for the higher incidence of ischemic outcomes observed in this population.

Background:\ud \ud The STICH trial showed superiority of coronary artery bypass plus medical treatment (CABG) over medical treatment alone (MED) in patients with left ventricular ejection fraction (LVEF) ≤35%. In previous publications, percutaneous coronary intervention (PCI) prior to CABG was associated with worse prognosis.\ud Objectives:\ud \ud The main purpose of this study was to analyse if prior PCI influenced outcomes in STICH.\ud Methods and results:\ud \ud Patients in the STICH trial (n = 1212), followed for a median time of 9.8 years, were included in the present analyses. In the total population, 156 had a prior PCI (74 and 82, respectively, in the MED and CABG groups). In those with vs. without prior PCI, the adjusted hazard-ratios (aHRs) were 0.92 (95% CI = 0.74–1.15) for all-cause mortality, 0.85 (95% CI = 0.64–1.11) for CV mortality, and 1.43 (95% CI = 1.15–1.77) for CV hospitalization. In the group randomized to CABG without prior PCI, the aHRs were 0.82 (95% CI = 0.70–0.95) for all-cause mortality, 0.75 (95% CI = 0.62–0.90) for CV mortality and 0.67 (95% CI = 0.56–0.80) for CV hospitalization. In the group randomized to CABG with prior PCI, the aHRs were 0.76 (95% CI = 0.50–1.15) for all-cause mortality, 0.81 (95% CI = 0.49–1.36) for CV mortality and 0.61 (95% CI = 0.41–0.90) for CV hospitalization. There was no evidence of interaction between randomized treatment and prior PCI for any endpoint (all adjusted p > 0.05).\ud Conclusion:\ud \ud In the STICH trial, prior PCI did not affect the outcomes of patients whether they were treated medically or surgically, and the superiority of CABG over MED remained unchanged regardless of prior PCI.\ud Clinical trial registration:\ud \ud Clinicaltrials.gov; Identifier: NCT00023595

Background: The efficacy of ticagrelor in the long-term post–ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remains uncertain.Objectives: The purpose o...

Background: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy. Methods: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest. Results: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72–0.99; P =0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88–1.13; P =0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81–1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event ( P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65–1.00; P =0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72–1.00; P =0.055) in patients with and without previous MI, respectively ( P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010). Conclusions: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

Recent reports have suggested that aspirin effect might be influenced by bodyweight, with decreased efficacy in heavier individuals. We investigated the influence of bodyweight on aspirin pharmacodynamics in two independent datasets of patients taking non-enteric coated aspirin 100 mg QD for coronary artery disease (CAD). In the first dataset, 368 patients had their platelet aggregation assessed using VerifyNow Aspirin and measured in Aspirin Reaction Units (ARU). In the second dataset, 70 patients had serum thromboxane B2 (TXB2) dosage assessed by an ELISA assay and measured in pg/mL. Platelet aggregation was independently associated with bodyweight, with 8.41 (95% CI 1.86–14.97; adjusted p-value = 0.012) increase in ARU for every 10 kg. Furthermore, the rate of non-response to aspirin (defined as ARU ≥ 550) was significantly associated with increased bodyweight (adjusted p-value = 0.007), with OR = 1.23 (95% CI 1.06–1.42) for every 10 kg. Similar results were found considering body mass index (in kg/m2), with 15.5 (95% CI 5.0 to 25.9; adjusted p-value = 0.004) increase in ARU for every 10 kg and non-response OR = 1.43 (95% CI 1.13 to 1.81, adjusted p-value = 0.003) for every 5 kg/m2. Moreover, serum TXB2 was higher in patients weighting more than 70 kg (222.6 ± 62.9 versus 194.9 ± 61.9 pg/mL; adjusted p-value = 0.018). In two different datasets of patients with CAD on non-enteric coated aspirin 100 mg QD, increased bodyweight was independently associated with impaired response to aspirin.

Aims To investigate the impact of patiromer on the serum potassium level and its ability to enable specified target doses of renin–angiotensin–aldosterone system inhibitor (RAASi) use in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results A total of 1642 patients with HFrEF and current or a history of RAASi-related hyperkalemia were screened and 1195 were enrolled in the run-in phase with patiromer and optimization of the RAASi therapy [≥50% recommended dose of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, and 50 mg of mineralocorticoid receptor antagonist (MRA) spironolactone or eplerenone]. Specified target doses of the RAASi therapy were achieved in 878 (84.6%) patients; 439 were randomized to patiromer and 439 to placebo. All patients, physicians, and outcome assessors were blinded to treatment assignment. The primary endpoint was between-group difference in the adjusted mean change in serum potassium. Five hierarchical secondary endpoints were assessed. At the end of treatment, the median (interquartile range) duration of follow-up was 27 (13–43) weeks, the adjusted mean change in potassium was +0.03 mmol/l in the patiromer group and +0.13 mmol/l in the placebo group [difference in the adjusted mean change between patiromer and placebo: −0.10 mmol/l (95% confidence interval, CI −0.13, 0.07); P < 0.001]. Risk of hyperkalemia >5.5 mmol/l [hazard ratio (HR) 0.63; 95% CI 0.45, 0.87; P = 0.006), reduction of MRA dose (HR 0.62; 95% CI 0.45, 0.87; P = 0.006), and total adjusted hyperkalemia events/100 person-years (77.7 vs. 118.2; HR 0.66; 95% CI 0.53, 0.81; P < 0.001) were lower with patiromer. Hyperkalemia-related morbidity-adjusted events (win ratio 1.53, P < 0.001) and total RAASi use score (win ratio 1.25, P = 0.048) favored the patiromer arm. Adverse events were similar between groups. Conclusion Concurrent use of patiromer and high-dose MRAs reduces the risk of recurrent hyperkalemia (ClinicalTrials.gov: NCT03888066).

Aims Patients with heart failure (HF) and iron deficiency experience poor health-related quality of life (HRQoL). We evaluated the impact of intravenous (IV) ferric carboxymaltose (FCM) vs. placebo on HRQoL for the AFFIRM-AHF population. Methods and results The baseline 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), which was completed for 1058 (535 and 523) patients in the FCM and placebo groups, respectively, was administered prior to randomization and at Weeks 2, 4, 6, 12, 24, 36, and 52. The baseline KCCQ-12 overall summary score (OSS) mean ± standard error was 38.7 ± 0.9 (FCM group) and 37.1 ± 0.8 (placebo group); corresponding values for the clinical summary score (CSS) were 40.9 ± 0.9 and 40.1 ± 0.9. At Week 2, changes in OSS and CSS were similar for FCM and placebo. From Week 4 to Week 24, patients assigned to FCM had significantly greater improvements in OSS and CSS scores vs. placebo [adjusted mean difference (95% confidence interval, CI) at Week 4: 2.9 (0.5–5.3, P = 0.018) for OSS and 2.8 (0.3–5.3, P = 0.029) for CSS; adjusted mean difference (95% CI) at Week 24: 3.0 (0.3–5.6, P = 0.028) for OSS and 2.9 (0.2–5.6, P = 0.035) for CSS]. At Week 52, the treatment effect had attenuated but remained in favour of FCM. Conclusion In iron-deficient patients with HF and left ventricular ejection fraction, Graphical Abstract

Digital, Background Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. Objectives In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. Methods ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was 13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43. Conclusions In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402), Ciencias Médicas y de la Salud

The KM3NeT Collaboration has already produced more than one thousand acquisition boards, used for building two deep-sea neutrino detectors at the bottom of the Mediterranean Sea, with the aim of instrumenting a volume of several cubic kilometers with light sensors to detect the Cherenkov radiation produced in neutrino interactions. The the so-called Digital Optical Modules, house the PMTs and the acquisition and control electronics of the module, the Central Logic Board, which includes a Xilinx FPGA and embedded soft processor. The present work presents the architecture and functionalities of the software embedded in the soft processor of the Central Logic Board., 5 pages (5 excluding references), 1 figure. VLVnT2021 proceeding contribution

Importance: Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients. Objective: To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient’s lifetime. Design, Setting, and Participants: Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months. Interventions: Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy. Main Outcomes and Measures: The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient’s lifetime for the primary outcome and the secondary outcome of death from any cause. Results: A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival. Conclusions and Relevance: These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF. Trial registration: ClinicalTrials.gov Identifier: NCT03036124.

Objectives: This study sought to investigate the efficacy and safety of dapagliflozin in Black and White patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure). Background: Black patients may respond differently to certain treatments for HFrEF than White patients. Methods: Patients with New York Heart Association functional class II to IV with an ejection fraction of ≤40% and elevated N-terminal pro–B-type natriuretic peptide were eligible for DAPA-HF. Because >99% of Black patients were randomized in the Americas, this post hoc analysis considered Black and White patients enrolled only in North and South America. The primary outcome was the composite of a worsening HF event (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. Results: Of the 4,744 patients randomized in DAPA-HF, 1,494 (31.5%) were enrolled in the Americas. Of these, 1,181 (79.0%) were White, and 225 (15.1%) were Black. Black patients had a higher rate of worsening HF events, but not mortality, compared with White patients. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint similarly in Black patients (HR: 0.62; 95% CI: 0.37-1.03) and White patients (HR: 0.68; 95% CI: 0.52-0.90; P-interaction = 0.70). Consistent benefits were observed for other prespecified outcomes, including the composite of total (first and repeat) HF hospitalizations and cardiovascular death (P-interaction = 0.43) and Kansas City Cardiomyopathy Questionnaire total symptom score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either Black or White patients. Conclusions: Dapagliflozin reduced the risk of worsening HF and cardiovascular death, and it improved symptoms, similarly in Black and White patients without an increase in adverse events. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124)

BackgroundThrombo-inflammation may contribute to morbidity and mortality in Covid-19. We hypothesized that therapeutic-dose anticoagulation may improve outcomes in non-critically ill patients hospitalized for Covid-19.MethodsIn an open-label adaptive multiplatform randomized controlled trial, non-critically ill patients hospitalized for Covid-19, defined by the absence of critical care-level organ support at enrollment, were randomized to a pragmatic strategy of therapeutic-dose anticoagulation with heparin or usual care pharmacological thromboprophylaxis. The primary outcome combined survival to hospital discharge and days free of organ support through 21 days, which was evaluated with Bayesian statistical models according to baseline D-dimer.ResultsThe trial was stopped when prespecified criteria for superiority were met for therapeutic-dose anticoagulation in groups defined by high (≥2-fold elevated) and low (ConclusionsIn non-critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increases the probability of survival to hospital discharge with reduced use of organ support.Trial registration numbers: NCT02735707, NCT04505774, NCT04359277, NCT04372589

As the current COVID-19 pandemic progresses, more symptoms and signals related to how the disease manifests in the human body arise in the literature. Skin lesions and coagulopathies may be confounding factors on routine care and patient management. We analyzed the metabolic and lipidic profile of the skin from COVID-19 patients using imprints in silica plates as a non-invasive alternative, in order to better understand the biochemical disturbances caused by SARS-CoV-2 in the skin. One hundred and one patients (64 COVID-19 positive patients and 37 control patients) were enrolled in this cross-sectional study from April 2020 to June 2020 during the first wave of COVID-19 in São Paulo, Brazil. Fourteen biomarkers were identified related to COVID-19 infection (7 increased and 7 decreased in COVID-19 patients). Remarkably, oleamide has shown promising performance, providing 79.0% of sensitivity on a receiver operating characteristic curve model. Species related to coagulation and immune system maintenance such as phosphatidylserines were decreased in COVID-19 patients; on the other hand, cytokine storm and immunomodulation may be affected by molecules increased in the COVID-19 group, particularly primary fatty acid amides and N-acylethanolamines, which are part of the endocannabinoid system. Our results show that skin imprints may be a useful, noninvasive strategy for COVID-19 screening, by electing a pool of biomarkers with diagnostic potential.

AIMS Patients surviving an acute myocardial infarction (AMI) are at risk of developing symptomatic heart failure (HF) or premature death. We hypothesized that sacubitril/valsartan, effective in the treatment of chronic HF, prevents development of HF and reduces cardiovascular death following high-risk AMI compared to a proven angiotensin-converting enzyme (ACE) inhibitor. This paper describes the study design and baseline characteristics of patients enrolled in the Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI) trial. METHODS AND RESULTS PARADISE-MI, a multinational (41 countries), double-blind, active-controlled trial, randomized patients within 0.5-7 days of presentation with index AMI to sacubitril/valsartan or ramipril. Transient pulmonary congestion and/or left ventricular ejection fraction (LVEF) ≤40% and at least one additional factor augmenting risk of HF or death (age ≥70 years, estimated glomerular filtration rate

Three types of wakefulness appeared along the vertebrate’s phylogeny and ontogeny: spinal-rhombencephalic in fish, brainstem-diencephalic in reptiles and cortical in mammals, in which the paralyzed spinal-rhombencephalic wake and the brainstem-diencephalic wake remain as REMS and NREMS The spinal-rhombencephalic and cortical types of wake are inherently anti-homeostatic. Animals must forage, reproduce, and survive to predation disregarding the environmental circumstances, hence temporarily forgetting the homeostatic regulation. After fulfilling the vital functions, the brainstem-diencephalic wake recovers the homeostatic control. The phasic signs of REMS are adaptive in immature mammals, serving for demanding heat, milk and defense to their mother. These advantages outweigh the REMS' poikilostasis in infants. The adults’ poikilostasis of REMS is harmless in thermoneutral environments but is mal-adaptive in aquatic environments in which REMS is reduced or even disappears. These exceptions explain the anomalous examples of REMS. An on-off hypothalamic switch homeostatically regulates the entrance and exit from REMS. Furthermore, the vital phasic signs of REMS depend on a second pontine proportional homeostatic control. Altogether, they regulate the expression of REMS.

COVID-19 is still placing a heavy health and financial burden worldwide. Impairment in patient screening and risk management plays a fundamental role on how governments and authorities are directing resources, planning reopening, as well as sanitary countermeasures, especially in regions where poverty is a major component in the equation. An efficient diagnostic method must be highly accurate, while having a cost-effective profile. We combined a machine learning-based algorithm with mass spectrometry to create an expeditious platform that discriminate COVID-19 in plasma samples within minutes, while also providing tools for risk assessment, to assist healthcare professionals in patient management and decision-making. A cross-sectional study enrolled 815 patients (442 COVID-19, 350 controls and 23 COVID-19 suspicious) from three Brazilian epicenters from April to July 2020. We were able to elect and identify 19 molecules related to the disease's pathophysiology and several discriminating features to patient's health-related outcomes. The method applied for COVID-19 diagnosis showed specificity >96% and sensitivity >83%, and specificity >80% and sensitivity >85% during risk assessment, both from blinded data. Our method introduced a new approach for COVID-19 screening, providing the indirect detection of infection through metabolites and contextualizing the findings with the disease's pathophysiology. The pairwise analysis of biomarkers brought robustness to the model developed using machine learning algorithms, transforming this screening approach in a tool with great potential for real-world application.

Aims: We examined the efficacy and safety of dapagliflozin, compared with placebo, according to aetiology in patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). Methods and results: Aetiology was investigator-reported and categorized as ischaemic or non-ischaemic. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. A total of 4744 patients were randomized in DAPA-HF, of whom 2674 (56.4%) patients had an ischaemic aetiology. Participants with an ischaemic aetiology had a higher risk of cardiovascular mortality [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.13–1.63], but lower risk of HF hospitalization (HR 0.83, 95% CI 0.70–0.98) than non-ischaemic patients. Compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death to a similar extent in both patients with ischaemic and non-ischaemic aetiology (HR 0.77, 95% CI 0.65–0.92, and HR 0.71, 95% CI 0.58–0.87, respectively; P for interaction = 0.55). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Dapagliflozin, as compared with placebo, increased the proportion of patients with an improvement of Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) of ≥5 points (P for interaction = 0.32) and decreased the proportion with a deterioration in KCCQ-TSS of ≥5 points (P for interaction = 0.76), irrespective of aetiology. Study drug discontinuation and serious adverse events were similar according to treatment groups, irrespective of aetiology. Conclusions: Dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, similarly in patients with ischaemic and non-ischaemic aetiology. In addition, dapagliflozin was safe and well-tolerated, irrespective of aetiology.

Introduction: Preclinical studies in ST elevation myocardial infarction (STEMI) indicate that high mechanical index impulses guided with transthoracic diagnostic ultrasound associated with intravenously administered microbubbles results in the dissolution of the thrombus (sonothrombolysis), improving coronary microcirculation and epicardial coronary recanalization rate. Hypothesis: Left atrial (LA) echocardiographic parameters are compromised in STEMI and can be accurately measured by two-dimensional echocardiography. To study the effect of sonotrombolysis on the LA pressure and volume we propose our study. Methods: A total of 100 patients were randomized, 50 for the control group and 50 for the therapy group. Echocardiographic analysis of LA pressure and volume were performed immediately before and after percutaneous coronary intervention (PCI), 72 hours, 1 month and 6 months of follow-up. LA pressure was classified in normal or elevated, depending on the grade of left ventricular diastolic disfunction (DD): normal diastolic function and DD grade 1 have normal LA pressure, and DD grades 2 and 3 have elevated LA pressure, according to the American and European guideline. LA volume was evaluated by Simpson method and indexed to the body surface area. Results: The LA pressure and volume had lower values in the therapy group after 6 months of PCI. The comparison of LA pressure between the therapy and control groups respectively was: before PCI (72% vs. 70% normal; 28% vs. 30% elevated; p=0.826), after PCI (68% vs. 65% normal; 32% vs. 35% elevated; p=0.777), 72 hours (75% vs. 62% normal; 25% vs. 38% elevated; p=0.147), 1 month (68% vs. 52% normal; 32% vs. 48% elevated; p=0.123) and 6 months (84% vs. 64% normal; 16% vs. 36% elevated; p=0.035). The comparison of LA volumes between the therapy and control groups respectively was: before PCI (19.0±6.2 vs. 22.4±9.8 ml/m 2 ; p=0.061), after PCI (22.8±7.9 vs. 24.4±12.1 ml/m 2 ; p=0.469), 72 hours (25.9±8.5 vs. 26.4±12.7 ml/m 2 ; p=0.815), 1 month (27.2±8.3 vs. 29.1±13.1 ml/m 2 ; p=0.410) and 6 months (26.7±7.5 vs. 33.1±14.9 ml/m 2 ; p=0.013). Conclusions: The use of sonothrombolysis as adjuvant therapy in STEMI patients results in better values of LA pressure and volume, demonstrating the benefit of using this new therapy.

Background Patients with multivessel or complex coronary artery disease (CAD) are at increased risk of atherothrombotic events. It has been suggested that these patients may derive an incremental benefit with more intense antiplatelet strategies, according to prior subgroup analyses from randomized clinical trials. However, whether there is any association between the presence and extension of multivessel CAD and platelet aggregability (PA) in patients with acute coronary syndromes (ACS) is unknown. Purpose To analyze the independent association between PA and presence of multivessel CAD in patients with ACS. Methods Patients with ACS on dual antiplatelet therapy (aspirin plus clopidogrel) were included in this study. Multivessel CAD was defined as the presence of significant ≥50% stenosis at two or more major epicardic vessels. Platelet aggregability was assessed by VerifyNow P2Y12 assay expressed in P2Y12 Reactivity Units (PRU) on the day of discharge from the coronary care unit. High On-treatment platelet reactivity (HPR) was defined as PRU ≥208. Stepwise linear and logistic regression models were applied to adjust for confounders. Models were adjusted for: age, sex, race, diabetes, hypertension, smoking, dyslipidemia, prior MI, prior PCI, prior CABG, prior HF, prior stroke and ACS phenotype (STEMI vs. Non-ST-segment elevation ACS). Results A total of 237 patients were included, among whom 143 (60.3%) had multivessel CAD at the coronary angiogram and 175 (73.8%) were submitted to PCI during index hospitalization. Patients with multivessel disease were older (mean age 64.8±12.1 vs. 58.9±11.2 years; p Conclusion In patients with ACS, the presence and extension of multivessel CAD were associated with higher levels of platelet aggregability and higher rates of high on-treatment platelet reactivity with clopidogrel. This finding may explain the incremental benefit with more intense antiplatelet therapies seen in this particular subgroup in prior clinical trials. Prevalence of HPR and extension of CAD Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Sao Paulo Research Foundation (FAPESP)

Background Previous studies have shown the safety of intravenous glycoprotein (GP) IIbIIIa inhibitors used as a bridging after ADP receptor blocker withdrawal in patients with stable coronary artery disease and previous percutaneous coronary interventions (PCI) undergoing cardiac or non-cardiac surgeries. However, there are few data analyzing GP IIbIIIa inhibitor bridging among patients with acute coronary syndromes (ACS) scheduled for coronary artery bypass graft (CABG) during the same hospitalization. Purpose To evaluate the safety of tirofiban bridging after clopidogrel withdraw in post-ACS patients schedule for CABG during the same hospitalization. Methods Fifty-six patients who underwent CABG after tirofiban bridging post-ACS (bridge group - BG) were compared to 56 sex and age-matched controls also submitted to same-hospitalization CABG post-ACS without bridging (control group - CG). All patients received aspirin plus clopidogrel for ACS; clopidogrel was withdrawn 5 to 7 days before CABG and aspirin was maintained during the whole perioperative period. The primary endpoint was chest tube output in the first 24h after CABG (CTO24h). We hypothesized that BG would be non-inferior to CG, with a non-inferiority margin of 25% in excess of CTO24h in the BG compared to the CG, based on prior literature data. Other exploratory analyses were: blood transfusions, number of red blood cells/patient and re-thoracotomy 24h after surgery. A multivariable linear regression model was developed considering CTO24h as dependent variable and adjusted for other eight co-variates, described in the figure. Results From the 112 patients included (75% men; mean age 60.2±9.3 years), in comparison with CG, BG had higher proportion of STEMI (80.0% vs. 28.6%, p0.99), mean number of red blood cells/patient (0.3±0.8 vs 0.5±1.2, p=0.35) or re-thoracotomy due to bleeding (5.4% vs 0%, p=0.24). Conclusion Among ACS patients submitted to urgent CABG after clopidogrel withdrawal, tirofiban bridging, compared to no bridging, was not associated with higher risk of bleeding in the first 24 hours after surgery. Our study suggests that tirofiban may be a safe therapy to patients with high risk of thrombotic complication (such as stent thrombosis or re-infarction) after clopidogrel withdraw. Figure 1 Funding Acknowledgement Type of funding source: None

Background Dual antiplatelet therapy (DAPT) is recommended for patients with acute coronary syndromes (ACS). Up to 15% are submitted to coronary artery bypass graft (CABG) during the hospitalization for the index event. However, as current guidelines recommend withdrawal of clopidogrel at least 5 days prior to CABG, this waiting time may increase hospital length of stay, thus potentially having negative impacts on costs and clinical outcomes. As previously presented at the ESC 2019 Congress, the PLAT-CABG study showed that the strategy to shortening CABG waiting time guided by platelet function test was non-inferior to the standard of care in terms of perioperative bleeding and led to shorter length of hospital stay among ACS patients. In this subanalysis, we present results regarding the in-hospital expenses for the two strategies. Purpose To determine, from the perspective of the Brazilian Government Health System (BGHS), the hospital expenses of patients undergoing CABG guided by platelet aggregability tests in comparison to the standard of care. Methods The PLAT-CABG study was a randomized and open label clinical trial testing a strategy of platelet aggregability-guided CABG after ACS versus standard-of-care. A total of 185 ACS patients on DAPT (aspirin plus clopidogrel) scheduled for on-pump or off-pump CABG were randomized to clopidogrel withdraw 5 to 7 days prior to CABG (control group) vs. daily measurements of platelet aggregability using Multiplate ADP-test (intervention group). Hospital cost (expressed in Brazilian currency - reais) subanalysis was pre-specified in the main trial statistical analysis plan. All patients had their hospital expenses covered by the BGHS and platelet aggregability tests costs were included in the analysis. Patients randomized to intervention group were allowed to undergo CABG when platelet aggregation recovered (pre-defined as Multiplate ≥46 AUC). In per protocol analysis, only patients who underwent CABG on the day after reaching the pre-specified aggregabilty cut point were analyzed. Results The main results are depicted in Figure 1. In the intention-to-treat analysis, median hospital expenses for the intervention group were R$15,202.33 and for the control group R$16,251.37 (mean difference of R$1,049.04, or 6.4%, P=0.014). In per protocol analysis, the mean hospital expenses for the intervention group were R$14,248.41 and for the control group R$ 16,039.55 (difference of R$ 1,791.14 or 11.2%, P=0.003). For an estimated 70,000 CABG procedures/year in Brazil, we estimate that the implementation of this routine would save up to R$125,370,000.00/year. Conclusion In patients with ACS taking DAPT, a strategy of platelet function-guided timing to CABG resulted in lower hospital expenses compared to a standard of care of waiting at least 5 days after clopidogrel withdrawal. Figure 1. Hospital expenses between groups Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Roche Diagnostica Brazil

ObjectiveTo assess associations of health-related quality of life (HRQoL) with patient profile, resource use, cardiovascular (CV) events and mortality in stable patients post-myocardial infarction (MI).MethodsThe global, prospective, observational TIGRIS Study enrolled 9126 patients 1–3 years post-MI. HRQoL was assessed at enrolment and 6-month intervals using the patient-reported EuroQol-5 dimension (EQ-5D) questionnaire, with scores anchored at 0 (worst possible) and 1 (perfect health). Resource use, CV events and mortality were recorded during 2-years’ follow-up. Regression models estimated the associations of index score at enrolment with patient characteristics, resource use, CV events and mortality over 2-years’ follow-up.ResultsAmong 8978 patients who completed the EQ-5D questionnaire, 52% reported ‘some’ or ‘severe’ problems on one or more health dimensions. Factors associated with a lower index score were: female sex, older age, obesity, smoking, higher heart rate, less formal education, presence of comorbidity (eg, angina, stroke), emergency room visit in the previous 6 months and non-ST-elevation MI as the index event. Compared with an index score of 1 at enrolment, a lower index score was associated with higher risk of all-cause death, with an adjusted rate ratio of 3.09 (95% CI 2.20 to 4.31), and of a CV event, with a rate ratio of 2.31 (95% CI 1.76 to 3.03). Patients with lower index score at enrolment had almost two times as many hospitalisations over 2-years’ follow-up.ConclusionsClinicians managing patients post-acute coronary syndrome should recognise that a poorer HRQoL is clearly linked to risk of hospitalisations, major CV events and death.Trial registration numberClinicalTrials.gov Registry (NCT01866904) (https://clinicaltrials.gov).

OBJECTIVES: Returning to work after an episode of acute coronary syndrome (ACS) is challenging for many patients, and has both personal and social impacts. There are limited data regarding the working status in the very long-term after ACS. METHODS: We retrospectively analyzed 1,632 patients who were working prior to hospitalization for ACS in a quaternary hospital and were followed-up for up to 17 years. Adjusted models were developed to analyze the variables independently associated with actively working at the last contact, and a prognostic predictive index for not working at follow-up was developed. RESULTS: The following variables were significantly and independently associated with actively working at the last contact: age>median (hazard-ratio [HR], 0.76, p

PurposeSARS-CoV-2 infection poses a global public health problem. There is a critical need for improvements in the noninvasive prognosis of COVID-19. We hypothesized that matrix-assisted laser desorption ionization mass spectrometry (MALDI-TOF MS) analysis combined with bottom-up proteomic analysis of plasma proteins might identify features to predict high and low risk cases of COVID-19.Patients and MethodsWe used MALDI-TOF MS to analyze plasma small proteins and peptides isolated using C18 micro-columns from a cohort containing a total of 117 cases of high (hospitalized) and low risk (outpatients) cases split into training (n = 88) and validation sets (n= 29). The plasma protein/peptide fingerprint obtained was used to train the algorithm before validation using a blinded test cohort.ResultsSeveral sample preparation, MS and data analysis parameters were optimized to achieve an overall accuracy of 85%, sensitivity of 90%, and specificity of 81% in the training set. In the blinded test set, this signature reached an overall accuracy of 93.1%, sensitivity of 87.5%, and specificity of 100%. From this signature, we identified two distinct regions in the MALDI-TOF profile belonging to the same proteoforms. A combination of 1D SDS-PAGE and quantitative bottom-up proteomic analysis allowed the identification of intact and truncated forms of serum amyloid A-1 and A-2 proteins. Conclusions: We found a plasma proteomic profile that discriminates against patients with high and low risk COVID-19. Proteomic analysis of C18-fractionated plasma may have a role in the noninvasive prognosis of COVID-19. Further validation will consolidate its clinical utility.Key messageWhat is the key question?Do individuals infected with SARS-CoV-2 harboring different degree of disease severity have a plasma protein profile that differentiate them and predict the COVID-19 outcome?What is the bottom line?In a series of 117 patients with COVID-19 divided in hospitalized (60) and outpatients (57), differential expression of serum amyloid A-1 (SAA1) and A-2 (SAA2) predict their outcome.Why read on?The high mortality rate in SARS-CoV-2 infected individuals requires accurate markers for predicting COVID-19 severity. Plasma levels of SAA1 and SAA2 indicate higher risk of hospitalization and can be used to improve COVID-19 monitoring and therapy.

Background: Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. Methods: An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death. Conclusion: Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.

Background Dual antiplatelet therapy is recommended for patients with acute coronary syndromes (ACS). Approximately 10% to 15% of these patients will undergo coronary artery bypass graft (CABG) surgery for index events, and current guidelines recommend stopping clopidogrel at least 5 days before CABG. This waiting time has clinical and economic implications. Objectives This study aimed to evaluate if a platelet reactivity-based strategy is noninferior to standard of care for 24-h post-CABG bleeding. Methods In this randomized, open label noninferiority trial, 190 patients admitted with ACS with indications for CABG and on aspirin and P2Y12 receptor inhibitors, were assigned to either control group, P2Y12 receptor inhibitor withdrawn 5 to 7 days before CABG, or intervention group, daily measurements of platelet reactivity by Multiplate analyzer (Roche Diagnostics GmbH, Vienna, Austria) with CABG planned the next working day after platelet reactivity normalization (pre-defined as ≥46 aggregation units). Results Within the first 24 h of CABG, the median chest tube drainage was 350 ml (interquartile range [IQR]: 250 to 475 ml) and 350 ml (IQR: 255 to 500 ml) in the intervention and control groups, respectively (p for noninferiority Conclusions A strategy based on platelet reactivity-guided is noninferior to the standard of care in patients with ACS awaiting CABG regarding peri-operative bleeding, significantly shortens the waiting time to CABG, and decreases hospital expenses. (Evaluation of Platelet Aggregability in the Release of CABG in Patients With ACS With DAPT; NCT02516267 )

COVID-19 is still placing a heavy health and financial burden worldwide. Impairments in patient screening and risk management play a fundamental role on how governments and authorities are directing resources, planning reopening, as well as sanitary countermeasures, especially in regions where poverty is a major component in the equation. An efficient diagnostic method must be highly accurate, while having a cost-effective profile.We combined a machine learning-based algorithm with instrumental analysis using mass spectrometry to create an expeditious platform that discriminate COVID-19 in plasma samples within minutes, while also providing tools for risk assessment, to assist healthcare professionals in patient management and decision-making. A cross-sectional study with 728 patients (369 confirmed COVID-19 and 359 controls) was enrolled from three Brazilian epicentres (São Paulo capital, São Paulo countryside and Manaus) in the months of April, May, June and July 2020.We were able to elect and identify 21 molecules that are related to the disease’s pathophysiology and 26 features to patient’s health-related outcomes. With specificity >97% and sensitivity >83% from blinded data, this screening approach is understood as a tool with great potential for real-world application.

Background and Objective In patients with atrial fibrillation following percutaneous coronary intervention, if a proton pump inhibitor is used, could that allow the use of warfarin triple therapy, or is there additional reduction in bleeding while using it with dual therapy? Methods The RE-DUAL PCI trial randomized 2725 patients with atrial fibrillation post-percutaneous coronary intervention to dabigatran dual therapy (110 or 150 mg twice daily, with clopidogrel or ticagrelor) or warfarin triple therapy (with clopidogrel or ticagrelor, and aspirin for 1–3 months). This prespecified subgroup analysis evaluated risks of a first major bleeding event or clinically relevant non-major bleeding event, all gastrointestinal bleeding, and a composite efficacy endpoint of all-cause mortality/thromboembolic event or unplanned revascularization according to baseline use of a proton pump inhibitor. Results Of 2678 analyzed patients, 1641 (61.3%) were receiving a proton pump inhibitor at baseline. Dabigatran 110 and 150 mg dual therapy reduced the risk of major bleeding events or clinically relevant non-major bleeding events vs warfarin triple therapy regardless of proton pump inhibitor use, with comparable risk of the composite efficacy endpoint (all interaction p values > 0.05). For gastrointestinal bleeding, no interaction was observed between study treatment and proton pump inhibitor use (interaction p values 0.84 and 0.62 for dabigatran 110 and 150 mg dual therapy, respectively, vs warfarin triple therapy). Conclusions Dabigatran 110 and 150 mg dual therapy reduced the risk of major bleeding events or clinically relevant non-major bleeding events vs warfarin triple therapy, regardless of proton pump inhibitor use at baseline, in patients with atrial fibrillation who underwent percutaneous coronary intervention. Risk of the composite efficacy endpoint appeared to be similar for dabigatran dual therapy vs warfarin triple therapy in patients receiving/not receiving a proton pump inhibitor. ClinicalTrials.gov unique identifier NCT02164864. Video abstract Electronic supplementary material The online version of this article (10.1007/s40265-020-01323-x) contains supplementary material, which is available to authorized users.

Background A proposed cause of dyspnea induced by ticagrelor is an increase in adenosine blood levels. Because caffeine is an adenosine antagonist, it can potentially improve drug tolerability with regard to dyspnea. Furthermore, association between caffeine and cardiovascular events is of clinical interest. Methods and Results This prespecified analysis used data from the PEGASUS TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54) trial, which randomized 21 162 patients with prior myocardial infarction to ticagrelor 60 mg or 90 mg or matching placebo (twice daily). Baseline caffeine intake in cups per week was prospectively collected for 9694 patients. Outcomes of interest included dyspnea, major adverse cardiovascular events (ie, the composite of cardiovascular death, myocardial infarction, or stroke), and arrhythmias. Dyspnea analyses considered the pooled ticagrelor group, whereas cardiovascular outcome analyses included patients from the 3 randomized arms. After adjustment, caffeine intake, compared with no intake, was not associated with lower rates of dyspnea in patients taking ticagrelor (adjusted hazard ratio (HR), 0.91; 95% CI , 0.76–1.10; P =0.34). There was no excess risk with caffeine for major adverse cardiovascular events (adjusted HR, 0.78; 95% CI, 0.63–0.98; P =0.031), sudden cardiac death (adjusted HR, 0.98; 95% CI, 0.57–1.70; P =0.95), or atrial fibrillation (adjusted odds ratio, 1.07; 95% CI, 0.56–2.04; P =0.84). Conclusions In patients taking ticagrelor for secondary prevention after myocardial infarction, caffeine intake at baseline was not associated with lower rates of dyspnea compared with no intake. Otherwise, caffeine appeared to be safe in this population, with no apparent increase in atherothrombotic events or clinically significant arrhythmias. Registration URL : https://www.clini​caltr​ials.gov ; Unique identifier: NCT 01225562.

Background: It has recently been demonstrated that high-energy diagnostic transthoracic ultrasound and intravenous microbubbles dissolve thrombi (sonothrombolysis) and increase angiographic recanalization rates in patients with ST-segment–elevation myocardial infarction. We aimed to study the effect of sonothrombolysis on the myocardial dynamics and infarct size obtained by real-time myocardial perfusion echocardiography and their value in preventing left ventricular remodeling. Methods: One hundred patients with ST-segment–elevation myocardial infarction were randomized to therapy (50 patients treated with sonothrombolysis and percutaneous coronary intervention) or control (50 patients treated with percutaneous coronary intervention only). Left ventricular volumes, ejection fraction, risk area (before treatment), myocardial perfusion defect over time (infarct size), and global longitudinal strain were determined by quantitative real-time myocardial perfusion echocardiography and speckle tracking echocardiography imaging. Results: Risk area was similar in the control and therapy groups (19.2±10.1% versus 20.7±8.9%; P =0.56) before treatment. The therapy group presented a behavior significantly different than control group over time ( P P =0.015). The left ventricular global longitudinal strain was higher in the therapy than control immediately after percutaneous coronary intervention (14.1±4.1% versus 12.0±3.3%; P =0.012), and this difference was maintained until 6 months (17.1±3.5% versus 13.6±3.6%; P P =0.026). Conclusions: Sonothrombolysis reduces microvascular obstruction and improves myocardial dynamics in patients with ST-segment–elevation myocardial infarction and is an independent predictor of left ventricular remodeling over time.

Sodium tungstate is an alternative to reduce hyperglycemia for the treatment of diabetes. In previous work, we showed that the administration of sodium tungstate increased the specific activity of salivary amylase in the parotid gland. Here, we investigated the effect of the administration of sodium tungstate on the lipid peroxidation and some antioxidant parameters in the submandibular (SM) and parotid (PA) salivary glands of streptozotocin (STZ)-induced diabetic rats. Thirty-two male Wistar rats were divided into four groups (n = 8, each): control (C), control treated with sodium tungstate (CT), diabetic (D), and diabetic treated with sodium tungstate (CT). Sodium tungstate (2 mg/ml) was administered to the STZ-induced diabetic rats for 15 days. Malondialdehyde (MDA), reduced (GSH) and oxidized (GSSG) glutathione, and blood glucose concentrations were quantified. In addition, superoxide dismutase (SOD) and catalase (CAT) activities were assessed. Results revealed that diabetes caused an increase in MDA concentration in both glands, a reduction in the SOD activity in SM, and an increase in catalase activity in PA glands. Administration of sodium tungstate reduced the blood glucose levels and normalized the SOD activity in the SM and MDA levels in both glands of the STZ-induced diabetic rats. Catalase activity was increased in PA glands of diabetic and tungstate-treated animals (p

Background There is limited information about the use of antithrombotic therapies and outcomes of Latin American (LatAm) subjects with atrial fibrillation. The global ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation Atrial Fibrillation–Thrombolysis In Myocardial Infarction 48) trial compared the efficacy and safety of edoxaban versus warfarin over a median follow-up of 2.8 years. Objectives The authors aimed to compare adjusted outcomes in Latin America versus outside Latin America and to compare outcomes stratified by anticoagulant treatment and region. Methods The authors analyzed clinical characteristics and outcomes, adjusted for baseline characteristics, the Human Development Index, and randomized treatment of 2,661 LatAm versus 18,444 non–Latin American subjects (nLAS). Results When compared with nLAS, LatAm subjects had a similar overall risk for stroke. After multivariate adjustment, the risks of stroke/systemic embolism (hazard ratio [HR]: 1.19; 95% confidence interval (CI): 0.96 to 1.47; p = 0.11) and major bleeding (HR: 1.10; 95% CI: 0.89 to 1.36; p = 0.39) were similar in LatAm and nLAS. LatAm subjects were at higher adjusted risk of death (HR: 1.48; 95% CI: 1.30 to 1.69; p Conclusions After multivariable adjustment, LatAm subjects with atrial fibrillation had higher rates of intracranial hemorrhage and death than nLAS. Outcomes with higher-dose edoxaban versus warfarin were at least as favorable in LatAm subjects as in nLAS, with an even greater reduction in hemorrhagic stroke seen in LatAm.

The role of beta-blockers in patients with acute coronary syndromes is mainly derived from studies including patients with ST-segment elevation myocardial infarction. Little is known about the use of beta-blockers and associated long-term clinical outcomes in patients with non-ST-elevation acute coronary syndromes (NSTEACS). We analyzed short- and long-term clinical outcomes of 2921 patients with NSTEACS using or not oral beta-blockers in the first 24 h of the acute coronary syndromes (ACS) presentation. The association between beta-blocker use and mortality was assessed using a propensity score adjusted analysis (N = 1378). Patients starting oral beta-blockers in the first 24 h of hospitalization, compared with patients who did not, had lower rates of in-hospital mortality (OR = 0.52, 95% CI 0.33 to 0.74, P = 0.002) and higher mean survival times in the long-term follow-up (11.86±0.4 years vs. 9.92±0.39 years, P

Background The safety and efficacy of ticagrelor in patients with ST-elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remain uncertain. Objectives The primary objective of the TicagRElor in pAtients with ST elevation myocardial infarction treated with Thrombolysis (TREAT) trial is to evaluate the short-term safety of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy. Key secondary objectives are to assess the safety and efficacy of ticagrelor compared with clopidogrel at 12-months. Design The TREAT trial is a multicenter, randomized, phase III, Prospective randomized open blinded end-point (PROBE) study that enrolled 3,799 patients in 152 sites from 10 countries. Following administration of fibrinolytic therapy patients were randomized to a loading dose of ticagrelor 180 mg or clopidogrel 300 mg followed by a maintenance dose of ticagrelor 90 mg twice daily or clopidogrel 75 mg/day for 12-months. The primary outcome is the rate of TIMI major bleeding at 30-days and will be assessed for non-inferiority using an intention-to-treat analysis. Co-treatments include aspirin and anticoagulants. Other evidence based therapies are also recommended. Secondary efficacy outcome include a composite of death from vascular causes, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack or other arterial thrombotic event. All-cause mortality as well as individual components of the combined efficacy endpoint will also be ascertained. Summary TREAT is an international randomized controlled trial comparing ticagrelor with clopidogrel in STEMI patients treated with fibrinolytic therapy. The results of this trial will inform clinical practice and international guidelines.

Although largely unrecognized by sleep scholars, sleeping is a pleasure. This report aims first, to fill the gap: sleep, like food, water and sex, is a primary reinforcer. The levels of extracellular mesolimbic dopamine show circadian oscillations and mark the "wanting" for pro-homeostatic stimuli. Further, the dopamine levels decrease during waking and are replenished during sleep, in opposition to sleep propensity. The wanting of sleep, therefore, may explain the homeostatic and circadian regulation of sleep. Accordingly, sleep onset occurs when the displeasure of excessive waking is maximal, coinciding with the minimal levels of mesolimbic dopamine. Reciprocally, sleep ends after having replenished the limbic dopamine levels. Given the direct relation between waking and mesolimbic dopamine, sleep must serve primarily to gain an efficient waking. Pleasant sleep (i.e. emotional sleep), can only exist in animals capable of feeling emotions. Therefore, although sleep-like states have been described in invertebrates and primitive vertebrates, the association sleep-pleasure clearly marks a difference between the sleep of homeothermic vertebrates and cool blooded animals.

Background Left ventricular ejection fraction (LVEF) is a major determinant of long-term prognosis after ST-segment elevation myocardial infarction (STEMI). STEMI patients with reduced LVEF have a poor prognosis, despite successful reperfusion and the use of renin-angiotensin-aldosterone inhibitors. Hypothesis Intracoronary infusion of bone marrow-derived mononuclear cells (BMMC) may improve LVEF in STEMI patients successfully reperfused. Methods The main inclusion criteria for this double-blind, randomized, multicenter study were patient age 30 to 80 years, LVEF ≤50%, successful angioplasty of infarct-related artery, and regional dysfunction in the infarct-related area analyzed before cell injection. Cardiac magnetic resonance imaging was used to assess LVEF, left ventricular volumes, and infarct size at 7 to 9 days and 6 months post-myocardial infarction. Results One hundred and twenty-one patients were included (66 patients in the BMMC group and 55 patients in the placebo group). The primary endpoint, mean LVEF, was similar between both groups at baseline (44.63% ± 10.74% vs 42.23% ± 10.33%; P = 0.21) and at 6 months (44.74% ± 12.95 % vs 43.50 ± 12.43%; P = 0.59). The groups were also similar regarding the difference between baseline and 6 months (0.11% ± 8.5% vs 1.27% ± 8.93%; P = 0.46). Other parameters of left ventricular remodeling, such as systolic and diastolic volumes, as well as infarct size, were also similar between groups. Conclusions In this randomized, multicenter, double-blind trial, BMMC intracoronary infusion did not improve left ventricular remodeling or decrease infarct size.

The long-term progression of coronary artery disease as defined by the natural disease course years after a myocardial infarction (MI) is an important but poorly studied area of clinical research. The long-Term rIsk, clinical manaGement, and healthcare Resource utilization of stable coronary artery dISease in post-myocardial infarction patients (TIGRIS) study was designed to address this knowledge gap by evaluating patient management and clinical outcomes following MI in different regions worldwide. TIGRIS (ClinicalTrials.gov Identifier: NCT01866904) is a multicenter, observational, prospective, longitudinal study enrolling patients with history of MI 1 to 3 years previously and high risk of developing atherothrombotic events in a general-practice setting. The primary objective of TIGRIS is to evaluate clinical events (time to first occurrence of any event from the composite cardiovascular endpoint of MI, unstable angina with urgent revascularization, stroke, or death from any cause), and healthcare resource utilization associated with hospitalization for these events (hospitalization duration and procedures) during follow-up. Overall, 9225 patients were enrolled between June 2013 and November 2014 and are being followed in 369 different centers worldwide. This will allow for the description of regional differences in patient characteristics, risk profiles, medical treatment patterns, clinical outcomes, and healthcare resource utilization. Patients will be followed for up to 3 years. Here we report the rationale, design, patient distribution, and selected baseline characteristics of the TIGRIS study. TIGRIS will describe real-world management, quality of life (self-reported health), and healthcare resource utilization for patients with stable coronary artery disease ≥1 year post-MI.

Background Recommendations for physical activity in patients with stable coronary heart disease (CHD) are based on modest evidence. Objectives The authors analyzed the association between self-reported exercise and mortality in patients with stable CHD. Methods A total of 15,486 patients from 39 countries with stable CHD who participated in the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) study completed questions at baseline on hours spent each week taking mild, moderate, and vigorous exercise. Associations between the volume of habitual exercise in metabolic equivalents of task hours/week and adverse outcomes during a median follow-up of 3.7 years were evaluated. Results A graded decrease in mortality occurred with increased habitual exercise that was steeper at lower compared with higher exercise levels. Doubling exercise volume was associated with lower all-cause mortality (unadjusted hazard ratio [HR]: 0.82; 95% confidence interval [CI]: 0.79 to 0.85; adjusting for covariates, HR: 0.90; 95% CI: 0.87 to 0.93). These associations were similar for cardiovascular mortality (unadjusted HR: 0.83; 95% CI: 0.80 to 0.87; adjusted HR: 0.92; 95% CI: 0.88 to 0.96), but myocardial infarction and stroke were not associated with exercise volume after adjusting for covariates. The association between decrease in mortality and greater physical activity was stronger in the subgroup of patients at higher risk estimated by the ABC-CHD (Age, Biomarkers, Clinical–Coronary Heart Disease) risk score (p for interaction = 0.0007). Conclusions In patients with stable CHD, more physical activity was associated with lower mortality. The largest benefits occurred between sedentary patient groups and between those with the highest mortality risk.

Raul C Maranhão,1,2 Maria C Guido,1 Aline D de Lima,1 Elaine R Tavares,1 Alyne F Marques,1 Marcelo D Tavares de Melo,3 Jose C Nicolau,3 Vera MC Salemi,3 Roberto Kalil-Filho3 1Laboratory of Metabolism and Lipids, 2Faculty of Pharmaceutical Sciences, 3Heart Failure Unit, Clinical Cardiology Division, Heart Institute (InCor), Medical School Hospital, University of São Paulo, São Paulo, Brazil Purpose: Acute myocardial infarction (MI) is accompanied by myocardial inflammation, fibrosis, and ventricular remodeling that, when excessive or not properly regulated, may lead to heart failure. Previously, lipid core nanoparticles (LDE) used as carriers of the anti-inflammatory drug methotrexate (MTX) produced an 80-fold increase in the cell uptake of MTX. LDE-MTX treatment reduced vessel inflammation and atheromatous lesions induced in rabbits by cholesterol feeding. The aim of the study was to investigate the effects of LDE-MTX on rats with MI, compared with commercial MTX treatment.Materials and methods: Thirty-eight Wistar rats underwent left coronary artery ligation and were treated with LDE-MTX, or with MTX (1 mg/kg intraperitoneally, once/week, starting 24 hours after surgery) or with LDE without drug (MI-controls). A sham-surgery group (n=12) was also included. Echocardiography was performed 24 hours and 6 weeks after surgery. The animals were euthanized and their hearts were analyzed for morphometry, protein expression, and confocal microscopy.Results: LDE-MTX treatment achieved a 40% improvement in left ventricular (LV) systolic function and reduced cardiac dilation and LV mass, as shown by echocardiography. LDE-MTX reduced the infarction size, myocyte hypertrophy and necrosis, number of inflammatory cells, and myocardial fibrosis, as shown by morphometric analysis. LDE-MTX increased antioxidant enzymes; decreased apoptosis, macrophages, reactive oxygen species production; and tissue hypoxia in non-infarcted myocardium. LDE-MTX increased adenosine bioavailability in the LV by increasing adenosine receptors and modulating adenosine catabolic enzymes. LDE-MTX increased the expression of myocardial vascular endothelium growth factor (VEGF) associated with adenosine release; this correlated not only with an increase in angiogenesis, but also with other parameters improved by LDE-MTX, suggesting that VEGF increase played an important role in the beneficial effects of LDE-MTX. Overall effects of commercial MTX were minor, and did not improve LV function or infarction size. Both treatments did not induce any toxicity. Conclusion: The remarkable improvement in heart function and reduction in infarction size achieved by LDE-MTX supports future clinical trials. Keywords: lipid particle, drug delivery, adenosine, VEGF, myocardial infarction&nbsp

Background: The risk of sudden cardiac death (SCD) in patients with heart failure after coronary artery bypass graft surgery (CABG) has not been examined in a contemporary clinical trial of surgical revascularization. This analysis describes the incidence, timing, and clinical predictors of SCD after CABG. Methods: Patients enrolled in the STICH trial (Surgical Treatment of Ischemic Heart Failure) who underwent CABG with or without surgical ventricular reconstruction were included. We excluded patients with prior implantable cardioverter-defibrillator and those randomized only to medical therapy. The primary outcome was SCD as adjudicated by a blinded committee. A Cox model was used to examine and identify predictors of SCD. The Fine and Gray method was used to estimate the incidence of SCD accounting for the competing risk of other deaths. Results: Over a median follow-up of 46 months, 113 of 1411 patients who received CABG without (n = 934) or with (n = 477) surgical ventricular reconstruction had SCD; 311 died of other causes. The mean left ventricular ejection fraction at enrollment was 28±9%. The 5-year cumulative incidence of SCD was 8.5%. Patients who had SCD and those who did not die were younger and had fewer comorbid conditions than did those who died of causes other than SCD. In the first 30 days after CABG, SCD (n=5) accounted for 7% of all deaths. The numerically greatest monthly rate of SCD was in the 31- to 90-day time period. In a multivariable analysis including baseline demographics, risk factors, coronary anatomy, and left ventricular function, end-systolic volume index and B-type natriuretic peptide were most strongly associated with SCD. Conclusions: The monthly risk of SCD shortly after CABG among patients with a low left ventricular ejection fraction is highest between the first and third months, suggesting that risk stratification for SCD should occur early in the postoperative period, particularly in patients with increased preoperative end-systolic volume index or B-type natriuretic peptide. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT0002359.

BACKGROUND: Evidence is lacking on long-term outcomes in unselected patients surviving the first year following myocardial infarction (MI). METHODS AND RESULTS: The TIGRIS (long-Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease in post-myocardial infarction patients) prospective registry enrolled 9176 eligible patients aged ≥50 years, 1-3 years post-MI, from 25 countries. All had ≥1 risk factor: age ≥ 65 years, diabetes mellitus, second prior MI, multivessel coronary artery disease, chronic kidney disease (CKD). Primary outcome was a composite of MI, unstable angina with urgent revascularization, stroke, or all-cause death at 2-year follow-up. Bleeding requiring hospitalization was also recorded. 9027 patients (98.4%) provided follow-up data: the primary outcome occurred in 621 (7.0%), all-cause mortality in 295 (3.3%), and bleeding in 109 (1.2%) patients. Events accrued linearly over time. In multivariable analyses, qualifying risk factors were associated with increased risk of primary outcome (incidence rate ratio [RR] per 100 patient-years [95% confidence interval]): CKD 2.06 (1.66, 2.55), second prior MI 1.71 (1.38, 2.10), diabetes mellitus 1.63 (1.39, 1.92), age ≥ 65 years 1.53 (1.28, 1.83), and multivessel disease 1.24 (1.05, 1.48). Risk of bleeding events was greater in older patients (vs