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BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been suggested to exert cardioprotective effects in patients with heart failure, possibly by improving the metabolism of ketone bodies in the myocardium. METHODS: This post hoc analysis of the EMMY trial investigated the changes in serum ß-hydroxybutyrate (3-ßOHB) levels after acute myocardial infarction (AMI) in response to 26-week of Empagliflozin therapy compared to the usual post-MI treatment. In addition, the association of baseline and repeated measurements of 3-ßOHB with cardiac parameters and the interaction effects of Empagliflozin were investigated. Cardiac parameters included N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), left ventricle end-systolic volume (LVESV), left ventricle end-diastolic volume (LVEDV), and left ventricular filling pressure (E/é ratio). RESULTS: The mean 3-ßOHB levels increased from baseline (46.2 ± 3.0 vs. 51.7 ± 2.7) to 6 weeks (48.8 ± 2.2 vs. 42.0 ± 2.3) and 26 weeks (49.3 ± 2.2 vs. 35.8 ± 1.9) in the Empagliflozin group compared to a consistent decline in placebo over 26 weeks (pinteraction < 0.001). Baseline and longitudinal measurements of 3-ßOHB were not significantly associated with NT-proBNP and E/é ratio. Baseline 3-ßOHB value was negatively associated with LVEF (coefficient: - 0.464, 95%CI - 0.863;- 0.065, p = 0.023), while an increase in its levels over time was positively associated with LVEF (0.595, 0.156;1.035, 0.008). The baseline 3-ßOHB was positively associated with LVESV (1.409, 0.186;2.632, 0.024) and LVEDV (0.640, - 1.170;- 2.449, 0.488), while an increase in its levels over time was negatively associated with these cardiac parameters (LVESV: - 2.099, - 3.443;- 0.755, 0.002; LVEDV: - 2.406, - 4.341;- 0.472, 0.015). Empagliflozin therapy appears to modify the association between 3-ßOHB, LVEF (pinteraction = 0.090), LVESV (pinteraction = 0.134), and LVEDV (pinteraction = 0.168), particularly at 26 weeks; however, the results were not statistically significant. CONCLUSION: This post hoc analysis showed that SGLT2i increased 3-ßOHB levels after AMI compared to placebo. Higher baseline 3-ßOHB levels were inversely associated with cardiac function at follow-up, whereas a sustained increase in 3-ßOHB levels over time improved these markers. This highlights the importance of investigating ketone body metabolism in different post-MI phases. Although more pronounced effect of 3-ßOHB on cardiac markers was observed in the SGLT2i group, further research is required to explore this interaction effect.
Assuntos
Ácido 3-Hidroxibutírico , Compostos Benzidrílicos , Biomarcadores , Glucosídeos , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Inibidores do Transportador 2 de Sódio-Glicose , Função Ventricular Esquerda , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Biomarcadores/sangue , Masculino , Feminino , Compostos Benzidrílicos/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Glucosídeos/uso terapêutico , Pessoa de Meia-Idade , Fatores de Tempo , Idoso , Resultado do Tratamento , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Ácido 3-Hidroxibutírico/sangue , Volume Sistólico/efeitos dos fármacosRESUMO
BACKGROUND: Pharmacological post-MI treatment is routinely initiated at intensive/cardiac care units. However, solid evidence for an early start of these therapies is only available for dual platelet therapy and statins, whereas data on beta blockers and RAAS inhibitors are heterogenous and mainly limited to STEMI and heart failure patients. Recently, the EMMY trial provided the first evidence on the beneficial effects of SGLT2 inhibitors (SGLT2i) when initiated early after PCI. In patients with type 2 diabetes mellitus, SGLT2i are considered "sick days drugs" and it, therefore, remains unclear if very early SGLT2i initiation following MI is as safe and effective as delayed initiation. METHODS AND RESULTS: The EMMY trial evaluated the effect of empagliflozin on NT-proBNP and functional and structural measurements. Within the Empagliflozin group, 22 (9.5%) received early treatment (< 24 h after PCI), 98 (42.2%) within a 24 to < 48 h window (intermediate), and 111 (48.1%) between 48 and 72 h (late). NT-proBNP levels declined by 63.5% (95%CI: - 69.1; - 48.1) in the early group compared to 61.0% (- 76.0; - 41.4) in the intermediate and 61.9% (- 70.8; - 45.7) in the late group (n.s.) within the Empagliflozin group with no significant treatment groups-initiation time interaction (pint = 0.96). Secondary endpoints of left ventricular function (LV-EF, e/e`) as well as structure (LVESD and LVEDD) were also comparable between the groups. No significant difference in severe adverse event rate between the initiation time groups was detected. CONCLUSION: Very early administration of SGLT2i after acute myocardial infarction does not show disadvantageous signals with respect to safety and appears to be as effective in reducing NT-proBNP as well as improving structural and functional LV markers as initiation after 2-3 days.
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Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Infarto do Miocárdio , Intervenção Coronária Percutânea , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/induzido quimicamente , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/complicações , Insuficiência Cardíaca/tratamento farmacológicoRESUMO
BACKGROUND: SGTL2-inhibitors are a cornerstone in the treatment of heart failure, but data on patients with acute myocardial infarction (AMI) is limited. The EMMY trial was the first to show a significant reduction in NTproBNP levels as well as improved cardiac structure and function in post-AMI patients treated with Empagliflozin compared to placebo. However, data on the potential impact of SGLT2-inhibitors on inflammatory biomarkers after AMI are scarce. MATERIALS AND METHODS: The EMMY trial is an investigator-initiated, multicentre, double-blind, placebo-controlled trial, which enrolled patients after AMI, receiving either 10 mg Empagliflozin once daily or placebo over a period of 26 weeks on top of standard guideline-recommended therapy starting within 72 h after percutaneous coronary intervention. In this post-hoc subgroup analysis of the EMMY trial, we investigated inflammatory biomarkers of 374 patients. The endpoints investigated were the mean change in inflammatory biomarkers such as high-sensitive c-reactive protein (hsCRP), interleukin-6 (IL-6), neutrophils, leukocytes, neutrophile/lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) from baseline to 26 weeks. RESULTS: Baseline median (interquartile ranges) IL-6 was 17.9 pg/mL (9.0-38.7), hsCRP 18.9 mg/L (11.2-37.1), neutrophil count 7.9 x G/L (6.2-10.1), leukocyte count 10.8 x G/L (9.1-12.8) and neutrophile/lymphocyte ratio (NLR) of 0.74 (0.67-0.80). At week 26, a significant mean reduction in inflammatory biomarkers was observed, being 35.1 ± 3.2% (p < 0.001) for IL-6, 57.4 ± 0.7% (p < 0.001) for hsCRP, 26.1 ± 0.7% (p < 0.001) for neutrophils, 20.5 ± 0.6% (p < 0.001) for leukocytes, 10.22 ± 0.50% (p < 0.001) for NLR, and - 2.53 ± 0.92% for PLR (p = 0.006) with no significant difference between Empagliflozin and placebo treatment. CONCLUSION: Trajectories of inflammatory biomarkers showed a pronounced decline after AMI, but Empagliflozin treatment did not impact this decline indicating no central role in blunted systemic inflammation mediating beneficial effects.
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Infarto do Miocárdio , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Transportador 2 de Glucose-Sódio , Proteína C-Reativa/metabolismo , Interleucina-6/metabolismo , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/tratamento farmacológico , Biomarcadores , Compostos Benzidrílicos/efeitos adversosRESUMO
In heart failure as well as in chronic kidney disease sodium-glucose cotransporter 2 (SGLT2) inhibitors have changed the landscape of medical therapy. Originally developed for use in diabetes, an unforeseen cardiovascular benefit extended SGLT2 inhibitor use from antihyperglycemic agents to cardiovascular and renal risk modifying agents. As their benefit in cardiovascular disease is independent from the diabetic state as well as the left ventricular ejection fraction it is the only class of therapy recommended throughout the spectrum of heart failure. Until very recently, the remaining gap in evidence has been data on the safety and efficacy of SGLT2 inhibitors in patients with acute myocardial infarction (MI) as former trials of SGLT2 inhibitors to date have excluded patients with recent ischemic events. As the first out of three trials conducted in post MI SGLT2 inhibitors therapy the EMMY trial was published. EMMY randomized 476 patients shortly after percutaneous intervention for recent large MI to either 10 mg of empagliflozin daily or placebo. The primary endpoint of changes in N-terminal pro brain natriuretic peptide (NT-proBNP) over 26 weeks as well as the functional and structural secondary endpoints were met. This provides first evidence of SGLT2 inhibitors-mediated beneficial results in this group of patients. We here discuss these results in the light of the two upcoming outcome trials (DAPA-MI and EMPACT-MI) with regard to the future role of this class of drugs early after MI.
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AIMS: Sodium-glucose co-transporter 2 inhibition reduces the risk of hospitalization for heart failure and for death in patients with symptomatic heart failure. However, trials investigating the effects of this drug class in patients following acute myocardial infarction are lacking. METHODS AND RESULTS: In this academic, multicentre, double-blind trial, patients (n = 476) with acute myocardial infarction accompanied by a large creatine kinase elevation (>800â IU/L) were randomly assigned to empagliflozin 10â mg or matching placebo once daily within 72â h of percutaneous coronary intervention. The primary outcome was the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) change over 26 weeks. Secondary outcomes included changes in echocardiographic parameters. Baseline median (interquartile range) NT-proBNP was 1294 (757-2246) pg/mL. NT-proBNP reduction was significantly greater in the empagliflozin group, compared with placebo, being 15% lower [95% confidence interval (CI) -4.4% to -23.6%] after adjusting for baseline NT-proBNP, sex, and diabetes status (P = 0.026). Absolute left-ventricular ejection fraction improvement was significantly greater (1.5%, 95% CI 0.2-2.9%, P = 0.029), mean E/e' reduction was 6.8% (95% CI 1.3-11.3%, P = 0.015) greater, and left-ventricular end-systolic and end-diastolic volumes were lower by 7.5â mL (95% CI 3.4-11.5â mL, P = 0.0003) and 9.7â mL (95% CI 3.7-15.7â mL, P = 0.0015), respectively, in the empagliflozin group, compared with placebo. Seven patients were hospitalized for heart failure (three in the empagliflozin group). Other predefined serious adverse events were rare and did not differ significantly between groups. CONCLUSION: In patients with a recent myocardial infarction, empagliflozin was associated with a significantly greater NT-proBNP reduction over 26 weeks, accompanied by a significant improvement in echocardiographic functional and structural parameters. CLINICALTRIALS.GOV REGISTRATION: NCT03087773.
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Insuficiência Cardíaca , Infarto do Miocárdio , Humanos , Biomarcadores , Insuficiência Cardíaca/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos/uso terapêutico , Volume Sistólico , Função Ventricular EsquerdaRESUMO
Sodium glucose cotransporter 2 (SGLT2) have proven profound positive effects in heart failure with reduced ejection fraction (HFrEF). These effects are independent from the presence of diabetes. Metabolic effects, antiinflammatory, and antifibrotic properties are discussed as underlying mechanisms. Despite a strong correlation of ventricular arrhythmias with HFrEF, the impact of ertugliflozin on the ventricular arrhythmic burden has not been investigated, yet. Therefore, the Ertugliflozin to Reduce Arrhythmic burden in ICD ± CRT patientS (ERASe) trial was designed to investigate the efficacy and safety of ertugliflozin in patients with reduced and midrange ejection fraction (EF) with or without diabetes. METHODS: Within a multicentre, national, randomized, double-blind, placebo-controlled, phase 3b trial we aim to enrol a total of 402 patients across Austria. Patients with reduced or midrange EF and ICD ± CRT therapy >3 months and previous ventricular tachycardia (at least 10 documented VT episodes within the last 12 months) are randomized in a 1:1 ratio to ertugliflozin (5 mg once daily orally administered) or matching placebo. The primary endpoint of the ERASe trial is to investigate the impact of ertugliflozin on total burden of ventricular arrhythmias. Further objectives will include number of therapeutic interventions of implanted devices, atrial fibrillation and heart failure biomarkers. CONCLUSION: The ERASe trial will be the first trial to test ertugliflozin in heart failure patients with nonpreserved ejection fraction and ongoing ICD ± CRT therapy regardless of their diabetic status. The ERASe trial may therefore extend the concept of SGLT2 inhibition to improve cardiac remodelling, including reduced arrhythmic burden. Trial registration Identifier EudraCT Nr. 2020-002581-14 / ClinicalTrials.gov Identifier: NCT04600921.
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Desfibriladores Implantáveis , Insuficiência Cardíaca , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Método Duplo-Cego , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/terapia , Humanos , Volume Sistólico/fisiologia , Resultado do Tratamento , Função Ventricular Esquerda/fisiologiaRESUMO
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are gaining ground as standard therapy for heart failure with a class-I recommendation in the recently updated heart failure guidelines from the European Society of Cardiology. Different gliflozins have shown impressive beneficial effects in patients with and without diabetes mellitus type 2, especially in reducing the rates for hospitalization for heart failure, yet little is known on their antiarrhythmic properties. Atrial and ventricular arrhythmias were reported by clinical outcome trials with SGLT2 inhibitors as adverse events, and SGLT2 inhibitors seemed to reduce the rate of arrhythmias compared to placebo treatment in those trials. Mechanistical links are mainly unrevealed, since hardly any experiments investigated their impact on arrhythmias. Prospective trials are currently ongoing, but no results have been published so far. Arrhythmias are common in the heart failure population, therefore the understanding of possible interactions with SGLT2 inhibitors is crucial. This review summarizes evidence from clinical data as well as the sparse experimental data of SGLT2 inhibitors and their effects on arrhythmias.
Assuntos
Antiarrítmicos/uso terapêutico , Arritmias Cardíacas , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Transportador 2 de Glucose-Sódio/metabolismo , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , HumanosRESUMO
The EMMY trial was a multicentre, investigator-initiated, placebo-controlled, double-blind trial, which enrolled 476 patients immediately following AMI and the first study demonstrating a significant reduction in NT-proBNP-levels as well as significant improvements in cardiac structure and function in patients after acute myocardial infarction treated with empagliflozin vs. placebo. However, hardly any data are available investigating the prognostic role of baseline electrocardiogram metrics in SGLT2-inhibitor-treated patients. This post-hoc analysis investigated the association of baseline ECG metrics collected in one centre of the trial (181 patients) with changes in structural and functional cardiac parameters as well as cardiac biomarkers in response to Empagliflozin treatment. A total of 181 patients (146 men; mean age 58 ± 14 years) were included. Median PQ-interval was 156 (IQR 144-174) milliseconds (ms), QRS width 92 (84-98) ms, QTc interval 453 (428-478) ms, Q-wave duration 45 (40-60) ms, Q-wave amplitude 0.40 (0.30-0.70) millivolt (mV), and heart rate was 71 (64-85) bpm. For functional cardiac parameters (LVEF and E/e') of the entire cohort, a greater decrease of E/e' from baseline to week 26 was observed in shorter QRS width (P = 0.005).Structural cardiac endpoints were only found to have a significant positive correlation between LVEDD and Q wave duration (P = 0.037). Higher heart rate was significantly correlated with better response in LVEF (P = 0.001), E/e' (P = 0.021), and NT-proBNP (P = 0.005). Empagliflozin-treatment showed no interaction with the results. Baseline ECG characteristics post AMI are neither predictive for beneficial NTproBNP effects of Empagliflozin post AMI, nor for functional or structural changes within 26 weeks post AMI.
Assuntos
Compostos Benzidrílicos , Biomarcadores , Ecocardiografia , Eletrocardiografia , Glucosídeos , Infarto do Miocárdio , Humanos , Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Feminino , Biomarcadores/sangue , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Idoso , Método Duplo-Cego , Peptídeo Natriurético Encefálico/sangue , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Fragmentos de Peptídeos/sangueRESUMO
The emerging European Health Data Space (EHDS) Regulation opens new prospects for large-scale sharing and re-use of health data. Yet, the proposed regulation suffers from two important limitations: it is designed to benefit the whole population with limited consideration for individuals, and the generation of secondary datasets from heterogeneous, unlinked patient data will remain burdensome. AIDAVA, a Horizon Europe project that started in September 2022, proposes to address both shortcomings by providing patients with an AI-based virtual assistant that maximises automation in the integration and transformation of their health data into an interoperable, longitudinal health record. This personal record can then be used to inform patient-related decisions at the point of care, whether this is the usual point of care or a possible cross-border point of care. The personal record can also be used to generate population datasets for research and policymaking. The proposed solution will enable a much-needed paradigm shift in health data management, implementing a 'curate once at patient level, use many times' approach, primarily for the benefit of patients and their care providers, but also for more efficient generation of high-quality secondary datasets. After 15 months, the project shows promising preliminary results in achieving automation in the integration and transformation of heterogeneous data of each individual patient, once the content of the data sources managed by the data holders has been formally described. Additionally, the conceptualization phase of the project identified a set of recommendations for the development of a patient-centric EHDS, significantly facilitating the generation of data for secondary use.
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BACKGROUND: Cardiogenic shock (CS) exhibits high (~50%) in-hospital mortality. The recently published Extracorporeal life Support in Cardiogenic Shock (ECLS-SHOCK) trial demonstrated the neutral effects of the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) on all-cause death, as well as on all secondary outcomes in subjects presenting with myocardial-infarction (MI)-related CS. Here, we compared ECLS-SHOCK eligibility criteria with a real-world cohort of CS patients. METHODS AND RESULTS: ECLS-SHOCK eligibility criteria were applied to a prospective single-center CS registry (the PREPARE CS registry) consisting of 557 patients who were consecutively admitted to the catheterization laboratory (cath lab) of the Medical University of Graz, Austria, due to CS (SCAI C-E). Overall use of mechanical circulatory support (MCS) in this cohort was 19%. Sixty-nine percent of the entire cohort had MI-related CS, 38% of whom would have met ECLS-SHOCK eligibility criteria, thus representing only 27% of the PREPARE CS registry. Exclusion from the ECLS-SHOCK trial was based on patients with initial lactate values below 3 mmol/L (n = 168; 43.6%), aged over 80 years (n = 65; 16.9%), and with a duration of cardiopulmonary resuscitation (CPR) exceeding 45 min (n = 22; 5.7%). The 30-day mortality of patients of the PREPARE CS registry who met the ECLS-SHOCK eligibility criteria was 57.0%, compared to 48.4% of patients in the ECLS-SHOCK trial. The patients' baseline characteristics, however, differed considerably with respect to type of infarction, age, and gender. CONCLUSIONS: In a real-world cohort of patients with MI-related CS, only 38% of patients met the eligibility criteria of the ECLS-SHOCK trial. Thus, the impact of the use of VA-ECMO on outcome parameters in MI-related CS, as observed in the ECLS-SHOCK trial, may differ in a more heterogeneous real-world CS population of the PREPARE CS registry.
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Patients with acute myocardial infarction are at high risk for developing heart failure due to scar development. Although regenerative approaches are evolving, consistent clinical benefits have not yet been reported. Treatment with dutogliptin, a second-generation DPP-4 inhibitor, in co-administration with filgrastim (G-CSF) has been shown to enhance endogenous repair mechanisms in experimental models. The REC-DUT-002 trial was a phase 2, multicenter, double-blind placebo-controlled trial which explored the safety, tolerability, and efficacy of dutogliptin and filgrastim in patients with ST-elevation Myocardial Infarction (STEMI). Patients (n = 47, 56.1 ± 10.7 years, 29% female) with STEMI, reduced left ventricular ejection fraction (EF ≤ 45%) and successful revascularization following primary PCI were randomized to receive either study treatment or matching placebo. Cardiac magnetic resonance imaging (cMRI) was performed within 72 h post-PCI and repeated after 3 months. The study was closed out early due to the SARS-CoV-2 pandemic. There was no statistically significant difference between the groups with respect to serious adverse events (SAE). Predefined mean changes within cMRI-derived functional and structural parameters from baseline to 90 days did not differ between placebo and treatment (left ventricular end-diastolic volume: +13.7 mL vs. +15.7 mL; LV-EF: +5.7% vs. +5.9%). Improvement in cardiac tissue health over time was noted in both groups: full-width at half-maximum late gadolinium enhancement (FWHM LGE) mass (placebo: -12.7 g, treatment: -19.9 g; p = 0.23). Concomitant treatment was well tolerated, and no safety issues were detected. Based on the results, the FDA and EMA have already approved an adequately powered large outcome trial.
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The sodium-glucose cotransporter 2 inhibitors (SGLT2i), empagliflozin, dapagliflozin, and canagliflozin, have shown impressive beneficial effects in patients with type 2 diabetes mellitus in mandatory cardiovascular outcome trials. Retrospective data analysis revealed signals that pointed towards positive effects independent of the antidiabetic effects. This could be confirmed for empagliflozin and dapagliflozin in chronic heart failure with reduced ejection fraction alone, where rates of hospitalization for heart failure and cumulative major adverse cardiovascular events were reduced to a similar extent in patients with and without diabetes mellitus as in corresponding outcome trials. Cardiac remodeling following myocardial infarction leads to heart failure with reduced ejection fraction in many patients and aggravates morbidity and mortality. Clinical data of SGLT2i treatment after acute myocardial infarction is sparse. This review focuses on available experimental data on the effects of SGLT2i used before, during, and after myocardial infarction as well as already published and currently ongoing clinical trials.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Infarto do Miocárdio , Inibidores do Transportador 2 de Sódio-Glicose , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose , Humanos , Infarto do Miocárdio/tratamento farmacológico , Estudos Retrospectivos , Sódio , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
OBJECTIVE: In previous research, a tool chain to simulate vehicle-pedestrian accidents from ordinary driving state to in-crash has been developed. This tool chain allows for injury criteria-based, vehicle-specific (geometry, stiffness, active safety systems, etc.) assessments. Due to the complex nature of the included finite element analysis (FEA) models, calculation times are very high. This is a major drawback for using FEA models in large-scale effectiveness assessment studies. Therefore, fast calculating surrogate models to approximate the relevant injury criteria as a function of pedestrian vehicle collision constellations have to be developed. METHOD: The development of surrogate models for head and leg injury criteria to overcome the problem of long calculation times while preserving high detail level of results for effectiveness analysis is shown in this article. These surrogate models are then used in the tool chain as time-efficient replacements for the FEA model to approximate the injury criteria values. The method consists of the following steps: Selection of suitable training data sets out of a large number of given collision constellations, detailed FEA calculations with the training data sets as input, and training of the surrogate models with the FEA model's input and output values. RESULTS: A separate surrogate model was created for each injury criterion, consisting of a response surface that maps the input parameters (i.e., leg impactor position and velocity) to the output value. In addition, a performance test comparing surrogate model predictions of additional collision constellations to the results of respective FEA calculations was carried out. The developed method allows for prediction of injury criteria based on impact constellation for a given vehicle. Because the surrogate models are specific to a certain vehicle, training has to be redone for a new vehicle. Still, there is a large benefit regarding calculation time when doing large-scale studies. CONCLUSION: The method can be used in prospective effectiveness assessment studies of new vehicle safety features and takes into account specific local features of a vehicle (geometry, stiffness, etc.) as well as external parameters (location and velocity of pedestrian impact). Furthermore, it can be easily extended to other injury criteria or accident scenarios; for example, cyclist accidents.