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This article, published in the journal Thoracic & Cardiovascular Surgeon, explores the relationship between early postoperative hypoalbuminemia and mortality and "days alive and out of hospital" (DAOH) after orthotopic heart transplantation (HTX). The study, conducted at the University Hospital Duesseldorf in Germany, included 212 patients who underwent HTX between 2011 and 2021. The results showed that patients with postoperative serum albumin levels below 3.0 g/dL had higher mortality rates and shorter DAOH. The authors suggest that further investigation is needed to determine the potential therapeutic role of early postoperative albumin substitution. [Extracted from the article]

Background: Cardiac risk evaluation prior to noncardiac surgery is fundamental to tailor peri-operative management to patient's estimated risk. Data on the degree of adherence to guidelines in patients at cardiovascular risk in Europe and factors influencing adherence are underexplored., Objectives: The aim of this analysis was to describe the degree of adherence to [2014 European Society of Cardiology (ESC)/European Society of Anaesthesiology (ESA) guidelines] recommendations on rest echocardiography [transthoracic echocardiography (TTE)] and to stress imaging prior to noncardiac surgery in a large European sample and to assess factors potentially affecting adherence., Design: Secondary analysis of a multicentre, international, prospective cohort study (MET-REPAIR)., Setting: Twenty-five European centres of all levels of care that enrolled patients between 2017 and 2020., Patients: With elevated cardiovascular risk undergoing in-hospital elective, noncardiac surgery., Main Outcome Measures: (Non)adherence to each pre-operative TTE and stress imaging recommendations classified as guideline-adherent, overuse and underuse. We performed descriptive analysis. To explore the impact of patients' sex, age, geographical region, and hospital teaching status, we conducted multivariate multinominal regression analysis., Results: Out of 15 983 patients, 15 529 were analysed (61% men, mean age 72 ± 8 years). Overuse (conduction in spite of class III) and underuse (nonconduction in spite of class I recommendation) for pre-operative TTE amounted to 16.6% (2542/15 344) and 6.6% (1015/15 344), respectively. Stress imaging overuse and underuse amounted to 1.7% (241/14 202) and 0.4% (52/14 202) respectively. Male sex, some age categories and some geographical regions were significantly associated with TTE overuse. Male sex and some regions were also associated with TTE underuse. Age and regions were associated with overuse of stress imaging. Male sex, age, and some regions were associated with stress imaging underuse., Conclusion: Adherence to pre-operative stress imaging recommendation was high. In contrast, adherence to TTE recommendations was moderate. Both patients' and geographical factors affected adherence to joint ESC/ESA guidelines., Trial Registration: NCT03016936., (Copyright © 2024 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Background: The American Heart Association (AHA) recently defined the cardiovascular-kidney-metabolic syndrome (CKM) as a new entity to address the complex interactions between heart, kidneys, and metabolism. The aim of this study was to assess the outcome impact of CKM syndrome in patients undergoing noncardiac surgery., Methods: This is a secondary analysis of a prospective international cohort study including patients aged ≥45 years with increased cardiovascular risk undergoing noncardiac surgery. Main exposure was CKM syndrome according to the AHA definition. The primary end point was a composite of major adverse cardiovascular events (MACE) 30 days after surgery. Secondary end points included all-cause mortality and non-MACE complications (Clavien-Dindo class ≥3)., Results: This analysis included 14,634 patients (60.8% male, mean age = 72±8 years). MACE occurred in 308 patients (2.1%), and 335 patients (2.3%) died. MACE incidence by CKM stage was as follows: CKM 0: 5/367 = 1.4% (95% confidence interval [CI], 0.4%-3.2%); CKM 1: 3/367 = 0.8% (95% CI, 0.2%-2.4%); CKM 2: 102/7440 = 1.4% (95% CI, 1.1%-1.7%); CKM 3: 27/953 = 2.8% (95% CI, 1.9%-4.1%); CKM 4a: 164/5357 = 3.1% (95% CI, 2.6%-3.6%); CKM 4b: 7/150 = 4.7% (95% CI, 1.9%-9.4%). In multivariate logistic regression, CKM stage ≥3 was independently associated with MACE, mortality, and non-MACE complications, respectively (MACE: OR 2.26 [95% CI, 1.78-2.87]; mortality: OR 1.42 [95% CI: 1.13 -1.78]; non-MACE complications: OR 1.11 [95% CI: 1.03-1.20])., Conclusion: The newly defined CKM syndrome is associated with increased morbidity and mortality after non-cardiac surgery. Thus, cardiovascular, renal, and metabolic disorders should be regarded in mutual context in this setting., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 International Anesthesia Research Society.)

Background: Impella™ is increasingly used in cardiogenic shock. However, thromboembolic and bleeding events are frequent during percutaneous mechanical circulatory support (pMCS)., Objective: Therefore, we aimed to explore the optimal anticoagulation regime for pMCS to prevent thromboembolism and bleedings., Methods: This hypothesis-generating multi-center cohort study investigated 170 patients with left-Impella™ support. We (A) compared bleeding/thrombotic events in two centers with therapeutic range (TR-aPTT) activated partial thromboplastin time (60-80s) and (B) compared events of these centers with one center with intermediate range aPTT (40-60s)., Results: After matching, there were no differences in patients' characteristics. In centers aiming at TR-aPTT, major bleeding was numerically lower with aPTT <60s within 48 h of left-Impella™ support, versus patients that achieved the aimed aPTT of ≥60s [aPTT ≥60s: 22 (37.3%) vs. aPTT<60s 14 (23.7%); Hazard ratio [HR], 0.62 (95%) CI, 0.28-1.38; p = 0.234]. Major cardiovascular and cerebrovascular adverse events (MACCE) did not differ between groups. In comparison of centers, TR-aPTT strategy showed higher major bleeding rates [TR: 8 (47.1%) vs. intermediate range: 1 (5.9%); HR, 0.06 (95%) CI, 0.01-0.45; p = 0.006]. MACCE were lower in the intermediate range aPTT group as well [TR 12 (70.6%) vs. intermediate range 5 (29.4%) HR, 0.32 (95%) CI, 0.11-0.92; p = 0.034]., Conclusion: This pilot analysis showed that lowering UFH-targets in left-Impella™ supported CS patients seems to be a safe and promising strategy for reducing major bleedings without increasing MACCE. This needs to be validated in larger, randomized clinical trials., Competing Interests: Declaration of competing interest Christophe Vandenbriele, Tim Balthazar, Bart Meyns and Ralf Westenfeld received training and research grants from Abiomed (USA). The remaining authors have nothing to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Hemodynamic stabilization plays a crucial role in the treatment of patients suffering from severe trauma. Current guidelines recommend the early administration of tranexamic acid (TXA) for bleeding control. While less blood loss can result in less end-organ damage, including myocardial injury, TXA also exhibits prothrombotic effects with potentially adverse myocardial effects. The aim of this study was to investigate the association between the administration of TXA and myocardial injury in patients with severe trauma. We conducted a monocentric cohort study including severely injured patients ≥ 18 years [defined by Injury severity score (ISS) ≥ 16], who were admitted to a tertiary care hospital between 2016 and 2019. Primary outcome measure was myocardial injury according to the fourth Universal Definition (= high sensitive troponin T ≥ 14 ng/l). Secondary endpoints were in-hospital major adverse cardiovascular events (MACE) and mortality. Main exposure was defined as administration of TXA during prehospital period. We conducted multivariate logistic regression models including predefined covariables. A total of 368 patients were screened. Among the 297 included patients (72% male, age. 55?21 years), 119 (40%) presented myocardial injury at hospital arrival. TXA was administered to 20/297 (7%) patients in the prehospital setting, and in 96/297 (32%) patients during pre-or in-hospital period. MACE incidence was 9% (26/297) and in-hospital mortality was 26% (76/297). The adjusted odds ratios (OR) for prehospital TXA and myocardial injury, MACE and mortality were 0.75 [95% confidence interval (CI): 0.25-2.23], 0.51 [95%CI: 0.06-4.30] and 0.84 [0.21-3.33], respectively. In the present cohort of patients suffering from severe trauma, prehospital TXA did not affect the incidence of myocardial injury., (© 2023. The Author(s).)

Objectives: In patients undergoing heart transplantation (HTX), preoperative liver impairment and consecutive hypoalbuminaemia are associated with increased mortality. The role of early postoperative hypoalbuminaemia after HTX is unclear. This study investigated the association between early postoperative hypoalbuminaemia and 1-year mortality as well as 'days alive and out of hospital' (DAOH) after HTX., Methods: This retrospective cohort study included patients who underwent HTX at the University Hospital Duesseldorf, Germany, between 2010 and 2022. The main exposure was serum albumin concentration at intensive care unit (ICU) arrival. The primary endpoints were mortality and DAOH within 1 year after surgery. Receiver operating characteristic (ROC) curve analysis was performed and logistic and quantile regression models with adjustment for 13 a priori defined clinical risk factors were conducted., Results: Out of 241 patients screened, 229 were included in the analysis (mean age 55 ± 11 years, 73% male). ROC analysis showed moderate discrimination for 1-year mortality by postoperative serum albumin after HTX [AUC = 0.74; 95% confidence interval (CI): 0.66-0.83]. The cutoff for serum albumin at ICU arrival was 3.0 g/dl. According to multivariate logistic and quantile regression, there were independent associations between hypoalbuminaemia and mortality/DAOH [odds ratio of 4.76 (95% CI: 1.94-11.67) and regression coefficient of -46.97 (95% CI: -83.81 to -10.13)]., Conclusions: Postoperative hypoalbuminaemia <3.0 g/dl is associated with 1-year mortality and reduced DAOH after HTX and therefore might be used for early postoperative risk re-assessment in clinical practice., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: The recently published ESAIC guidelines highlight the clinical value of cardiac troponins (cTn) and B‑type natriuretic peptides (BNP) for risk assessment in patients undergoing noncardiac surgery., Objective: Summary of the ESAIC guideline recommendations., Material and Methods: The evidence for the recommendations was extracted from studies that investigated the perioperative role of cTn and BNP as prognostic factors, for risk prediction and for therapeutic guidance. To collate this evidence 12 relevant endpoints as well as risk benefit analyses of systematic screening were considered to issue the strength of the recommendations., Results: The body of evidence for these guidelines was based on 115 studies. The evidence varied significantly across the 12 predefined endpoints. Additionally, there was a gradient in evidence for the use of cTn and BNP as prognostic factors, for risk prediction and for therapeutic guidance. The guidelines issue a weak recommendation for the use of preoperative, postoperative and combined measurement of cTn as well as for preoperative BNP measurement to assess the prognosis. For risk prediction a weak recommendation was formulated for combined and postoperative cTn and preoperative BNP measurements. No recommendation could be given for the evidence on biomarkers as data were very limited., Conclusion: Both cTn and BNP can be used as prognostic factors or to predict the risk for selected endpoints. Therapeutic interventions should not be guided by cardiac biomarker levels., (© 2023. The Author(s).)

Background: In recent years, there has been increasing focus on the use of cardiac biomarkers in patients undergoing noncardiac surgery., Aims: The aim of this focused guideline was to provide updated guidance regarding the pre-, post- and combined pre-and postoperative use of cardiac troponin and B-type natriuretic peptides in adult patients undergoing noncardiac surgery., Methods: The guidelines were prepared using Grading of Recommendations Assessment Development and Evaluation (GRADE) methodology. This included the definition of critical outcomes, a systematic literature search, appraisal of certainty of evidence, evaluation of biomarker measurement in terms of the balance of desirable and undesirable effects including clinical outcomes, resource use, health inequality, stakeholder acceptance, and implementation. The panel differentiated between three different scopes of applications: cardiac biomarkers as prognostic factors, as tools for risk prediction, and for biomarker-enhanced management strategies., Results: In a modified Delphi process, the task force defined 12 critical outcomes. The systematic literature search resulted in over 25,000 hits, of which 115 full-text articles formed the body of evidence for recommendations. The evidence appraisal indicated heterogeneity in the certainty of evidence across critical outcomes. Further, there was relevant gradient in the certainty of evidence across the three scopes of application. Recommendations were issued and if this was not possible due to limited evidence, clinical practice statements were produced., Conclusion: The ESAIC focused guidelines provide guidance on the perioperative use of cardiac troponin and B-type natriuretic peptides in patients undergoing noncardiac surgery, for three different scopes of application., (Copyright © 2023 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Purpose: During resuscitation of patients with severe trauma, guidelines recommend permissive hypotension prior to surgical bleeding control. However, hypotension may be associated with reduced organ perfusion and multiple organ dysfunction, e.g. myocardial injury. The association between hypotension and myocardial injury in trauma patients is underexplored. We hypothesized that hypotension is associated with myocardial injury in this population., Materials and Methods: This retrospective study included patients ≥ 18 years suffering from severe trauma [defined as Injury Severity Score (ISS) ≥ 16] that were treated in the emergency department resuscitation room between 2016 and 2019. Primary endpoint was the incidence of myocardial injury defined as high-sensitive troponin T > 14 ng/l. Main exposure was the duration of arterial hypotension during resuscitation period defined as mean arterial pressure < 65 mmHg., Results: Out of 368 patients screened, 343 were analyzed (73% male, age: 55 ± 21, ISS: 28 ± 12). Myocardial injury was detected in 143 (42%) patients. Overall in-hospital mortality was 26%. Multivariate binary logistic regression with forced entry of nine predefined covariables revealed an odds ratio of 1.29 [95% confidence interval 1.16-1.44]; p = 0.012) for the association between the duration of hypotension and myocardial injury., Conclusion: The duration of hypotension during resuscitation period is independently associated with the incidence of myocardial injury in patients with severe trauma., (© 2022. The Author(s).)

Background: Orthotopic heart transplantation (HTX) is the gold standard to treat end-stage heart failure. Numerous risk stratification tools have been developed in the past years. However, their clinical utility is limited by their poor discriminative ability. High sensitivity troponin T (hsTnT) is the most specific biomarker to detect myocardial cell injury. However, its prognostic relevance after HTX is not fully elucidated. Thus, this study evaluated the predictive value of postoperative hsTnT for 1-year survival and days alive and out of hospital (DAOH) after HTX., Methods: This retrospective cohort study included patients who underwent HTX at the University Hospital Duesseldorf, Germany between 2011 and 2021. The main exposure was hsTnT concentration at 48 h after HTX. The primary endpoints were mortality and DAOH within 1 year after surgery. Receiver operating characteristic (ROC) curve analysis, logistic regression model and linear regression with adjustment for risk index for mortality prediction after cardiac transplantation (IMPACT) were performed., Results: Out of 231 patients screened, 212 were included into analysis (mean age 55 ± 11 years, 73% male). One-year mortality was 19.7% (40 patients) and median DAOH was 298 days (229-322). ROC analysis revealed strongest discrimination for mortality by hsTnT at 48 h after HTX [AUC = 0.79 95% CI 0.71-0.87]. According to Youden Index, the cutoff for hsTnT at 48 h and mortality was 1640 ng/l. After adjustment for IMPACT score multivariate logistic and linear regression showed independent associations between hsTnT and mortality/DAOH with odds ratio of 8.10 [95%CI 2.99-21.89] and unstandardized regression coefficient of -1.54 [95%CI -2.02 to -1.06], respectively., Conclusion: Postoperative hsTnT might be suitable as an early prognostic marker after HTX and is independently associated with 1-year mortality and poor DAOH., (© 2023. The Author(s).)

Background: Antithrombotic regimen in patients on oral anticoagulation (OAC) post-percutaneous coronary intervention (PCI) is challenging. At least, one antiplatelet agent in combination with OAC is recommended after PCI for 6-12 months. Clopidogrel is used most frequently in this setting. However, data comparing P2Y12 inhibition with clopidogrel versus cyclooxygenase inhibition by acetylsalicylic acid (ASA, aspirin) is missing. It is well known that the antiplatelet effects of ASA and clopidogrel are frequently impaired (high on-treatment platelet reactivity [HTPR]). In this pilot investigation, we compared the antiplatelet effects of clopidogrel versus ASA., Methods: In this retrospective single-center database analysis, we investigated platelet reactivity by light transmission aggregometry in patients under different antiplatelet regimes. Results were presented as maximum of aggregation (MoA). HTPR to ASA and to clopidogrel were assessed., Results: 755 patients were enrolled. 677 were on ASA, 521 were on clopidogrel, and 198 had OAC. Overall mean age was 73 ± 13.4 years, and 458 (60.7%) were male. HTPR to ASA occurred in 94/677 patients (13.9%), and mean arachidonic acid-induced MoA was 14.15 ± 19.04%. HTPR to clopidogrel occurred in 241/521 patients (46.3%), and mean adenosine diphosphate-induced MoA was 50.06 ± 20.42%. HTPR to clopidogrel was significantly more frequent than HTPR to ASA; single antiplatelet therapy (SAPT)-mono ASA: 27/199 (13.6%) versus mono clopidogrel: 6/18 (33.3%); p = 0.037; SAPT with OAC-OAC with ASA: 8/35 (22.9%) versus OAC with clopidogrel: 27/60 (45%); p = 0.046. Same difference in HTPR contingency could be shown in subgroups of dual antiplatelet therapy and ASA + clopidogrel + OAC therapy., Conclusion: Impaired pharmacodynamic response to clopidogrel was more frequent as HTPR to ASA. Hence, ASA should be tested in combination with OAC post-PCI., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: Severe trauma potentially results in end-organ damage such as myocardial injury. Data suggest that myocardial injury is associated with increased mortality in this cohort, but the association with the incidence of in-hospital major adverse cardiac events (MACE) remains undetermined., Methods: Retrospective cohort study including adult patients with severe trauma treated at the University Hospital Duesseldorf between January 2016 and December 2019. The main exposure was myocardial injury at presentation. Endpoints were in-hospital incidence of MACE and incidence of acute kidney injury (AKI) within 72 h. Discrimination of hsTnT for MACE and AKI was examined by the receiver operating characteristic curve (ROC) and the area under the curve (AUC). We conducted multivariate logistic regression analysis., Results: We included 353 patients in our final analysis (72.5% male (256/353), age: 55 ± 21 years). The AUC for hsTnT and MACE was 0.68 [95% confidence interval (CI): 0.59-0.78]. The AUC for hsTnT and AKI was 0.64 [95% (CI): 0.55-0.72]. The adjusted odds ratio (OR) for myocardial injury and MACE was 2.97 [95% (CI): 1.31-6.72], and it was 2.14 [95% (CI): 1.03-4.46] for myocardial injury and AKI., Conclusion: Myocardial injury at presentation in patients with severe trauma is independently associated with the incidence of in-hospital MACE and AKI.

The two main surgical options to treat end-stage heart failure are heart transplantation (HTx) or left ventricular assist device (LVAD) implantation. In hemodynamically stable patients, the decision for HTx listing with or without LVADs is challenging. We analyzed the impact of both options on days alive and out of hospital (DAOH) and survival. This retrospective study screened all patients with HTx or LVAD implantation between 2010 and 2020. The main inclusion criterion was hemodynamic stability defined as independence of intravenous inotropic/vasoactive support at decision. Propensity score matching (PSM) was performed. The primary endpoint was DAOH within one year after the decision. Secondary endpoints included survival, duration until HTx, and hospitalizations. In total, 187 patients received HTx and 227 patients underwent LVAD implantation. There were 21 bridge-to-transplant (BTT)-LVAD patients (implantation less than a month after HTx listing or listing after implantation) and 44 HTx-waiting patients included. PSM identified 17 matched pairs. Median DAOH at one year was not significantly different between the groups (BTT-LVAD: median 281, IQR 89; HTx waiting: median 329, IQR 74; p = 0.448). Secondary endpoints did not differ significantly. Our data suggest that BTT-LVAD implantation may not be favorable in terms of DAOH within one year for hemodynamically stable patients compared to waiting for HTx. Further investigations on quality of life and long-term outcomes are warranted.

The adverse impact of common diseases like diabetes mellitus and acute hyperglycemia on morbidity and mortality from myocardial infarction (MI) has been well documented over the past years of research. In the clinical setting, the relationship between blood glucose and mortality appears linear, with amplifying risk associated with increasing blood glucose levels. Further, this seems to be independent of a diagnosis of diabetes. In the experimental setting, various comorbidities seem to impact ischemic and pharmacological conditioning strategies, protecting the heart against ischemia and reperfusion injury. In this translational experimental approach from bedside to bench, we set out to determine whether acute and/or prolonged hyperglycemia have an influence on the protective effect of transferred human RIPC-plasma and, therefore, might obstruct translation into the clinical setting. Control and RIPC plasma of young healthy men were transferred to isolated hearts of young male Wistar rats in vitro. Plasma was administered before global ischemia under either short hyperglycemic (HGs Con, HGs RIPC) conditions, prolonged hyperglycemia (HGl Con, HGl RIPC), or under normoglycemia (Con, RIPC). Infarct sizes were determined by TTC staining. Control hearts showed an infarct size of 55 ± 7%. Preconditioning with transferred RIPC plasma under normoglycemia significantly reduced infarct size to 25 ± 4% (p < 0.05 vs. Con). Under acute hyperglycemia, control hearts showed an infarct size of 63 ± 5%. Applying RIPC plasma under short hyperglycemic conditions led to a significant infarct size reduction of 41 ± 4% (p < 0.05 vs. HGs Con). However, the cardioprotective effect of RIPC plasma under normoglycemia was significantly stronger compared with acute hyperglycemic conditions (RIPC vs. HGs RIPC; p < 0.05). Prolonged hyperglycemia (HGl RIPC) completely abolished the cardioprotective effect of RIPC plasma (infarct size 60 ± 7%; p < 0.05 vs. HGl Con; HGl Con 59 ± 5%).

The number of patients waiting for heart transplantation (HTX) is increasing. Thus, identification of outcome-relevant factors is crucial. This study aimed to identify perioperative factors associated with days alive and out of hospital (DAOH)-a patient-centered outcome to quantify life impact-after HTX. This retrospective cohort study screened 187 patients who underwent HTX at university hospital Duesseldorf, Germany from September 2010 to December 2020. The primary endpoint was DAOH at 1 year. Risk factors for mortality after HTX were assessed in univariate analysis. Variables with significant association were entered into multivariable quantile regression. In total, 175 patients were included into analysis. Median DAOH at 1 year was 295 (223-322) days. In univariate analysis the following variables were associated with reduced DAOH: recipient or donor diabetes pre-HTX, renal replacement therapy (RRT), VA-ECMO therapy, recipient body mass index, recipient estimated glomerular filtration rate (eGFR) and postoperative duration of mechanical ventilation. After adjustment, mechanical ventilation, RRT, eGFR and recipient diabetes showed significant independent association with DAOH. This study identified risk factors associated with reduced DAOH at 1-year after HTX. These findings might complement existing data for outcome of patients undergoing HTX., (© 2022. The Author(s).)

Introduction: Hemodynamic assessment is crucial after heart transplantation (HTX) or left ventricular assist device (LVAD) implantation. Gold-standard is invasive assessment via thermodilution (TD). Noninvasive pulse contour analysis (NPCA) is a new technology that is supposed to determine hemodynamics completely noninvasive. We aimed to validate this technology in HTX and LVAD patients and conducted a prospective single-center cohort study., Methods: Patients after HTX or LVAD implantation underwent right heart catheterization including TD. NPCA using the CNAP Monitor (V.5.2.14; CNSystems Medizintechnik AG, Graz, Austria) was performed simultaneously. Three TD measurements were compared with simultaneous NPCA measurements for hemodynamic assessment. To describe the agreement between TD and NPCA, Bland-Altman analysis was done., Results: In total, 28 patients were prospectively enrolled (HTX: n = 10, LVAD: n = 18). Bland-Altman analysis revealed a mean bias of +1.05 l/min (limits of agreement ± 4.09 l/min, percentage error 62.1%) for cardiac output (CO). In LVAD patients, no adequate NPCA signal could be obtained. In 5 patients (27.8%), any NPCA signal could be detected, but was considered as low signal quality., Conclusion: In conclusion, according to our limited data in a small cohort of HTX and LVAD patients, NPCA using the CNAP Monitor seems not to be suitable for noninvasive evaluation of the hemodynamic status., Competing Interests: The authors have declared that no competing interests exist.

The impact of aortic stenosis on platelet reactivity is unclear. Previous studies reported contradicting results. The reason for this is unknown. It is known that flow alterations enhance platelet reactivity. A steep left ventricular-aortic angle (LV-AO-angle) is associated with turbulent flow in the aorta ascendens. Therefore, in this study, we hypothesized that LV-AO-angle is associated with platelet reactivity in patients with severe aortic stenosis. We included 289 patients with severe aortic stenosis and performed cardiac computertomography to assess the LV-AO-angle. Platelet function was evaluated by light transmission aggregometry. Platelet reactivity was higher in patients with a steep LV-AO-angle (ADP: <160°: 66.99% ± 20.72% vs. ≥160°: 60.66% ± 19.85%, P  = 0.009; collagen: <160°: 78.67% ± 13.19% vs. ≥160°: 73.85% ± 14.44%, P  = 0.003). Using Spearman correlation, ADP and collagen-induced aggregation was associated with LV-AO-angle (ADP: r  = -0.19, P  = 0.0009, R2  = 0.022; collagen: r  = -0.21, P  = 0.0004, R2  = 0.027). Apart from platelet reactivity, body weight, history of myocardial infarction and other factors were associated with steep LV-AO-angle. However, multivariate cox-regression (including body weight, comorbidities, history of MI and cardiac surgery, kidney function and laboratory parameters) revealed that LV-AO angle was a robust predictor of ADP and collagen-induced platelet aggregation. Steep LV-AO-angle is associated with enhanced platelet reactivity in patients with aortic stenosis. This could be the reason of contradicting results regarding platelet function in patients with aortic stenosis in previous studies. In addition, enhanced platelet reactivity in steep LV-AO-angle aortic stenosis patients might be a promising target in pathogenesis of aortic stenosis., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Implantation of left ventricular assist devices (LVADs) as a bridge to transplant or as destination therapy is increasing. The selection of suitable patients and outcome assessment belong to the key challenges. Mortality has traditionally been a focus of research in this field, but literature on quality of life is very limited. This study aimed to identify perioperative factors influencing patients' life as measured by days alive and out of hospital (DAOH) in the first year after LVAD implantation., Methods and Results: This retrospective single-centre cohort study screened 227 patients who underwent LVAD implantation at the University Hospital Duesseldorf, Germany, between 2010 and 2020. First, the influence of 10 prespecified variables on DAOH was investigated by univariate analysis. Second, multivariate quantile regression was conducted including all factors with significant influence on DAOH in the univariate model. Additionally, the impact of all variables on 1 year mortality was investigated using Kaplan-Meier curves to oppose DAOH and mortality. In total, 221 patients were included into analysis. As pre-operative factors, chronic kidney disease (CKD), pre-operative mechanical circulatory support (pMCS), and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) stadium < 3 were associated with lower DAOH at 1 year [CKD: 280 (155-322) vs. 230 (0-219), P = 0.0286; pMCS: 294 (155-325) vs. 243 (0-293), P = 0.0004; INTERMACS 1: 218 (0-293) vs. INTERMACS 2: 264 (6-320) vs. INTERMACS 3: 299 (228-325) vs. INTERMACS 4: 313 (247-332), P ≤ 0.0001]. Intra-operative additional implantation of a right ventricular assist device (RVAD) was also associated with lower DAOH [RVAD: 290 (160-325) vs. 174 (0-277), P ≤ 0.0001]. As post-operative values that were associated with lower DAOH, dialysis and tracheotomy could be identified [dialysis: 300 (252-326) vs. 186 (0-300), P ≤ 0.0001; tracheotomy: 292 (139-325) vs. 168 (0-269), P ≤ 0.0001]. Multivariate analysis revealed that all of these factors besides pMCS were independently associated with DAOH. According to Kaplan-Meier analysis, only post-operative dialysis was significantly associated with increased mortality at 1 year (survival: no dialysis 89.4% vs. dialysis 70.1%, hazard ratio: 0.56, 95% confidence interval: 0.33-0.94; P = 0.031)., Conclusions: The results of this study indicate that there can be a clear discrepancy between hard endpoints such as mortality and more patient-centred outcomes reflecting life impact. DAOH may relevantly contribute to a more comprehensive selection process and outcome assessment in LVAD patients., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Purpose: Severe trauma can lead to end organ damages of varying severity, including myocardial injury. In the non-cardiac surgery setting, there is extensive evidence that perioperative myocardial injury is associated with increased morbidity and mortality. The impact of myocardial injury on outcome after severe trauma has not been investigated adequately yet. We hypothesized that myocardial injury is associated with increased in-hospital mortality in patients with severe trauma., Materials/methods: This retrospective cohort study included patients ≥ 18 years with severe trauma [defined as injury severity score (ISS) ≥ 16] that were admitted to the resuscitation room of the Emergency Department of the University Hospital Duesseldorf, Germany, between 2016 and 2019. The main endpoint was in-hospital mortality. Main exposure was myocardial injury at arrival [defined as high-sensitive troponin T (hsTnT) > 14 ng/l]. For statistical analysis, receiver operating characteristic curve (ROC) and multivariate binary logistic regression were performed., Results: Out of 368 patients, 353 were included into statistical analysis (72.5% male, age: 55 ± 21, ISS: 28 ± 12). Overall in-hospital mortality was 26.1%. Myocardial injury at presentation was detected in 149 (42.2%) patients. In-hospital mortality of patients with and without myocardial injury at presentation was 45% versus 12.3%, respectively. The area under the curve (AUC) for hsTnT and mortality was 0.76 [95% confidence interval (CI) 0.71-0.82]. The adjusted odds ratio of myocardial injury for in-hospital mortality was 2.27 ([95%CI 1.16-4.45]; p = 0.017)., Conclusion: Myocardial injury after severe trauma is common and independently associated with in-hospital mortality. Thus, hsTnT might serve as a new prognostic marker in this cohort., (© 2021. The Author(s).)

Background: The number of patients treated with extracorporeal membrane oxygenation (ECMO) devices is increasing. Anticoagulation therapy is crucial to prevent thrombosis during ECMO therapy. Predominantly, heparin has been used as primary anticoagulant but direct thrombin inhibitors (DTI) have been established as alternatives. The aim of this systematic review and meta-analysis was to evaluate clinical outcomes in patients treated with heparin compared to different DTI during ECMO., Methods: A systematic search was conducted. Full scientific articles were sought for inclusion if heparin anticoagulation was compared to DTI (argatroban/bivalirudin) in ECMO patients. Risk of bias was assessed by Newcastle Ottawa scale. Primary endpoint was in-hospital mortality. Bleeding events, thrombotic events, hours of ECMO support, days of hospital stay, percentage of time within therapeutic range and time to therapeutic range were extracted from full texts as secondary endpoints. Results were presented as Forrest-plots. GRADE was used for confidence assessment in outcomes., Results: Systematic search identified 4.385 records, thereof 18 retrospective studies for a total of 1942 patients, complied with the predefined eligibility criteria:15 studies investigated bivalirudin and 3 studies investigated argatroban versus heparin. Risk of bias was high for most studies. In-hospital mortality, major bleeding events and pump-related thrombosis were less frequent in DTI group as compared to heparin [mortality-OR 0.69, 95% CI 0.54-0.86; major bleeding-OR 0.48, 95% CI 0.29-0.81; pump thrombosis-OR 0.55, 95% CI 0.40-0.76]. Additionally, percentage of time within therapeutic range was higher for DTI [SMD 0.54, 95% CI 0.14-0.94]. GRADE approach revealed a very low level of certainty for each outcome., Conclusion: In this meta-analysis, DTI and especially bivalirudin showed beneficial effects on clinical outcomes in ECMO patients as compared to heparin. However, due to the lack of randomized trials, certainty of evidence is low., Trial Registration: This systematic review and meta-analysis was prospectively registered at PROSPERO data base (reference number CRD42021237252 )., (© 2022. The Author(s).)

Thromboembolism is frequent in infective endocarditis (IE). However, the optimal antithrombotic regimen in IE is unknown. Staphylococcus aureus (SA) is the leading cause of IE. First studies emphasize increased platelet reactivity by SA. In this pilot study, we hypothesized that platelet reactivity is increased in patients with SA- IE, which could be abrogated by antiplatelet medication. We conducted a prospective, observatory, single-center cohort study in 114 patients with IE, with four cohorts: (1) SA coagulase positive IE without aspirin (ASA) medication, (2) coagulase negative IE without ASA, (3) SA coagulase positive IE with ASA, (4) coagulase negative IE with ASA. Platelet function was measured by Multiplate electrode aggregometry, blood clotting by ROTEM thromboelastometry. Bleeding events were assessed according to TIMI classification. In ASA-naïve patients, aggregation with ADP was increased with coag. pos. IE (coagulase negative: 39.47 ± 4.13 AUC vs. coagulase positive: 59.46 ± 8.19 AUC, p = 0.0219). This was abrogated with ASA medication (coagulase negative: 42.4 ± 4.67 AUC vs. coagulase positive: 45.11 ± 6.063 AUC p = 0.7824). Aspirin did not increase bleeding in SA positive patients. However, in SA negative patients with aspirin, red blood cell transfusions were enhanced. SA coagulase positive IE is associated with increased platelet reactivity. This could be abrogated by aspirin without increased bleeding risk. The results of this pilot study suggest that ASA might be beneficial in SA coagulase positive IE. This needs to be confirmed in clinical trials., (© 2022. The Author(s).)

Background: The number of patients waiting for heart transplantation (HTX) is increasing. Optimizing the use of all available donor hearts is crucial. While mortality seems not to be affected by donor cardiopulmonary resuscitation (CPR), the impact of donor CPR on days alive and out of hospital (DAOH) is unclear., Methods: This retrospective study included adults who underwent HTX at the University Hospital Duesseldorf, Germany from 2010-2020. Main exposure was donor-CPR. Secondary exposure was the length of CPR. The primary endpoint was DAOH at one year., Results: A total of 187 patients were screened and 171 patients remained for statistical analysis. One-year mortality was 18.7%. The median DAOH at one year was 295 days (interquartile range 206-322 days). Forty-two patients (24.6%) received donor-CPR hearts. The median length of CPR was 15 (9-21) minutes. There was no significant difference in DAOH between patients with donor-CPR hearts versus patients with no-CPR hearts (CPR: 291 days (211-318 days) vs. no-CPR: 295 days (215-324 days); p = 0.619). Multivariate linear regression revealed that there was no association between length of CPR and DAOH (unstandardized coefficients B: -0.06, standard error: 0.81, 95% CI -1.65-1.53, p = 0.943)., Conclusions: Donor CPR status and length of CPR are not associated with reduced DAOH at one year after HTX.

Aims: Primary graft dysfunction (PGD) is a feared complication after heart transplantation (HTX). HTX patients frequently receive veno-arterial extracorporeal membrane oxygenation (VA-ECMO) until graft recovery. Long-term mortality of patients weaned from VA-ECMO after HTX is comparable with non-ECMO patients. However, impact on quality of life is unknown. This study investigated days alive and out of hospital (DAOH) as patient-centred outcome in HTX patients at 1 year after surgery., Methods and Results: This retrospective single-centre cohort study included patients who underwent HTX at the University Hospital Düsseldorf, Germany, from 2010 to 2020. Main exposure was VA-ECMO due to PGD. VA-ECMO and non-VA-ECMO patients were compared regarding the primary endpoint DAOH at 1 year after HTX. Subgroup analysis for patients weaned from VA-ECMO was performed. In total, 144 patients were included into analysis; 1 year mortality was significantly lower in non-ECMO patients [non-ECMO 14.3% (14/98) vs. VA-ECMO 34.8% (16/46), adjusted hazard ratio: 0.32, 95% confidence interval: 0.15-0.74; P = 0.002]. Mortality did not differ significantly between patients weaned from VA-ECMO and non-ECMO patients [non-ECMO 14.3% (14/98) vs. VA-ECMO (weaned) 18.9% (7/37), adjusted hazard ratio: 0.72, 95% confidence interval: 0.27-1.90; P = 0.48]. DAOH were significantly higher in non-ECMO patients compared with VA-ECMO patients and patients weaned from VA-ECMO [non-ECMO vs. VA-ECMO: median 310 (inter-quartile range 277-327) days vs. 243 (0-288) days; P < 0.0001; non-ECMO vs. VA-ECMO (weaned): 310 (277-327) days vs. 253 (208-299) days; P < 0.0001]. These results were still significant after multivariable adjustment with forced entry of predefined covariables., Conclusions: Despite similar survival rates, VA-ECMO due to PGD has a relevant life impact as defined by DAOH in the first year after HTX. As a more patient-centred endpoint, DAOH may contribute to a more comprehensive assessment of outcome in HTX patients., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is increasing, but mortality remains high. Early assessment of prognosis is challenging and valid markers are lacking. This study aimed to investigate Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte-Ratio (PLR) and Procalcitonin (PCT) for early assessment of prognosis in patients undergoing VA-ECMO. This retrospective single-center cohort study included 344 consecutive patients ≥ 18 years who underwent VA-ECMO due to cardiogenic shock. Main exposures were NLR, PLR and PCT measured within 24 h after VA-ECMO initiation. The primary endpoint was all-cause in-hospital mortality. In total, 92 patients were included into final analysis (71.7% male, age 57 ± 14 years). In-hospital mortality rate was 48.9%. Receiver operating characteristics (ROC) curve revealed an area under the curve (AUC) of 0.65 [95% confidence interval (CI) 0.53-0.76] for NLR. The AUCs of PLR and PCT were 0.47 [95%CI 0.35-0.59] and 0.54 [95%CI 0.42-0.66], respectively. Binary logistic regression showed an adjusted odds ratio of 3.32 [95%CI 1.13-9.76] for NLR, 1.0 [95%CI 0.998-1.002] for PLR and 1.02 [95%CI 0.99-1.05] for PCT. NLR is independently associated with in-hospital mortality in patients undergoing VA-ECMO. However, discriminative ability is weak. PLR and PCT seem not to be suitable for this purpose., (© 2022. The Author(s).)

Objectives: Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard of care in patients with peripheral artery disease (PAD) after percutaneous transluminal angioplasty (PTA). However, high on treatment platelet reactivity (HTPR) to DAPT is frequent and associated with major adverse limb events (MALE) in PAD patients. Nevertheless, association of MALE and HTPR in patients with critical limb ischemia (CLI) is not known. Moreover, comorbidities might confound response to antiplatelet medication further. Hence, in this trial we analyzed pharmacodynamic responses to DAPT and clinical events in CLI patients post PTA., Methods: In this prospective single center pilot analysis, we included 71 CLI patients. Patients received DAPT after PTA. Antiplatelet effect were measured by light transmission aggregometry (LTA) and vasodilator-stimulated protein phosphorylation assay (VASP). MALE, major adverse cardiac and cerebrovascular events (MACCE) and BARC bleeding within 12 months follow-up were assessed., Results: Mean age of patients was 73.37 ± 7.36 years and 47 (66.2%) were male. Overall HTPR appeared in 46 patients (64.8%). MALE and MACCE showed no differences between patients with and patients without HTPR. However, bleeding was higher in patients with sufficient pharmacodynamic response to DAPT (Bleeding - HTPR: 13.4% vs. no HTPR: 36.0%; log-rank HR: 0.32; 95% CI 0.1079 to 0.9396 p = 0.0217). This finding remained robust in multivariate analysis., Conclusion: HTPR to DAPT is frequent in CLI patients. However, bleeding was higher in patients with sufficient response to DAPT. Ischemic events did not differ. Hence, CLI patients might benefit from an alternative antithrombotic approach., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Vaping emerges as alternative to standard tobacco smoking. However, there is evidence for critical cardiovascular, gastrointestinal and respiratory side effects. Nevertheless, long-term vaping effects on thrombocyte reactivity have not been investigated. Therefore, we investigated the influence of vaping on thrombocyte reactivity in comparison to standard smoking and non-smoking., Methods: Platelet function was measured by Multiplate Impedance Aggregometry as area under the curve (AUC). Smoking habits and characteristics were assessed by questionnaire. Results were analyzed using inverse probability of treatment weighting (IPTW) and conventional t-tests to test for robustness., Results: After IPTW adjustment, participants in all groups were balanced by age, gender, body height and weight. Collagen-induced aggregation was higher in vapers compared to non-smokers (non-smokers 52.55 ± 23.97 vs. vapers 66.63 ± 18.96 AUC, p = 0.002) and to smokers (vapers vs. smokers 49.50 ± 26.05 AUC, p < 0.0001). ADP-induced aggregation in vapers was higher compared to non-smokers (non-smokers 33.16 ± 16.61 vs. vapers 45.27 ± 18.67 AUC, p = 0.001) and was numerically increased compared to smokers (vapers vs. smokers 40.09 ± 19.80 AUC, p = 0.08). These findings remained robust in t-test analysis., Conclusion: This study provides first evidence that vaping leads to enhanced platelet reactivity compared to standard smoking and non-smoking. This suggests health effects of vaping might be more severe than previously assumed. Whether this effect translates to clinical outcome with a higher incidence of major cardiovascular events, should be evaluated in large-scaled clinical studies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background:  Transcatheter aortic valve implantation (TAVI) is an evolving treatment of severe aortic valve stenosis. However, thromboembolic events such as stroke are common, predominantly early after TAVI. Optimal periprocedural antithrombotic regime is unknown. Especially, as antithrombotic medication enhances bleeding risk, thrombin generation and platelet function are crucial in the pathogenesis of ischemic events. However, the impact of the TAVI procedure on thrombin formation and platelet reactivity is not known by now., Methods:  We evaluated thrombin levels using thrombin-antithrombin (TAT) complexes and prothrombin fragments (PTFs) using enzyme-linked immunosorbent assay. Furthermore, platelet reactivity was measured via light transmission aggregometry before and 2 hours after TAVI in 198 patients., Results:  TAT complexes and PTF F1 + 2 substantially increased during TAVI. Postprocedurally, TAT complexes and PTF were significantly higher after TAVI compared with percutaneous coronary intervention due to acute myocardial infarction, while preprocedural TAT complexes and PTF F1 + 2 did not differ. In contrast, platelet reactivity was not altered early after TAVI. Only adenosine diphosphate-induced aggregation was reduced, reflecting preprocedural loading with clopidogrel., Conclusion:  In this pilot study, we were able to demonstrate that thrombin generation is significantly increased early after TAVI, while platelet function is not affected. Increased thrombin concentrations may contribute to the high risk of postprocedural thromboembolic events. This leads to the hypothesis that extended peri-interventional anticoagulation early after TAVI may be an approach to reduce thromboembolic events., Competing Interests: None declared., (Thieme. All rights reserved.)

Acute kidney injury (AKI), requiring renal replacement therapy (RRT). is a serious complication after orthotopic heart transplantation (HTX). In patients with preexisting impaired renal function, postoperative AKI is unsurprising. However, even in patients with preserved renal function, AKI requiring RRT is frequent. Therefore, this study aimed to identify risk factors associated with postoperative AKI requiring RRT after HTX in this sub-cohort. This retrospective cohort study included patients ≥ 18 years of age with preserved renal function (defined as preoperative glomerular filtration rate ≥ 60 mL/min) who underwent HTX between 2010 and 2021. In total, 107 patients were included in the analysis (mean age 52 ± 12 years, 78.5% male, 45.8% AKI requiring RRT). Based on univariate logistic regression, use of extracorporeal membrane oxygenation, postoperative infection, levosimendan therapy, duration of norepinephrine (NE) therapy and maximum daily increase in tacrolimus plasma levels were chosen to be included into multivariate analysis. Duration of NE therapy and maximum daily increase in tacrolimus plasma levels remained as independent significant risk factors (NE: OR 1.01, 95%CI: 1.00-1.02, p = 0.005; increase in tacrolimus plasma level: OR 1.18, 95%CI: 1.01-1.37, p = 0.036). In conclusion, this study identified long NE therapy and maximum daily increase in tacrolimus plasma levels as risk factors for AKI requiring RRT in HTX patients with preserved renal function.

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) supports patients suffering from refractory cardiogenic shock. Thromboembolic complications (TeC) are common in VA-ECMO patients and are associated with increased morbidity and mortality. Valid markers to predict TeC in VA-ECMO patients are lacking. The present study investigated the predictive value of baseline Fibrinogen-Albumin-Ratio (FAR) for in-hospital TeC in patients undergoing VA-ECMO. This retrospective cohort study included patients who underwent VA-ECMO therapy due to cardiogenic shock at the University Hospital Duesseldorf, Germany between 2011 and 2018. Main exposure was baseline FAR measured at initiation of VA-ECMO therapy. The primary endpoint was the in-hospital incidence of TeC. In total, 344 patients were included into analysis (74.7% male, mean age 59 ± 14 years). The in-hospital incidence of TeC was 34%. Receiver operating characteristics (ROC) curve of FAR for in-hospital TeC revealed an area under the curve of 0.67 [95% confidence interval (CI) 0.61-0.74]. Youden index determined a cutoff of 130 for baseline FAR. Multivariate logistic regression revealed an adjusted odds-ratio of 3.72 [95% CI 2.26-6.14] for the association between FAR and TeC. Baseline FAR is independently associated with in-hospital TeC in patients undergoing VA-ECMO. Thus, FAR might contribute to the prediction of TeC in this cohort., (© 2021. The Author(s).)

Background: Guidelines recommend the PRECISE-DAPT (PD) score to adapt duration of dual antiplatelet therapy due to bleeding risk. However, there is first evidence that PD predicts mortality and ischemic events as well., Methods: We investigated PD Score in 994 patients after percutaneous coronary intervention (PCI). PD was correlated with clinically frequently used scores. Major adverse cardiac and cerebrovascular events (MACCE) and Thrombolysis in Myocardial Infarction (TIMI) bleeding were assessed during one-year follow-up., Results: 524 patients had PD < 25 and 470 patients PD ≥ 25 (47%). Rate of major and minor bleeding was higher in the PD ≥ 25 group (major bleeding: Hazard ratio [HR] 2.9, 95% confidence interval [Cl] 1.01-8.16, p = 0.049; minor bleeding: HR 3.94, 95% Cl 1.36-9.19, p = 0.0096). Rate of MACCE, death and myocardial infarction were higher as well (MACCE: HR 2.0, 95% Cl 1.52-2.71, p < 0.0001; death: HR 3.9, 95% Cl 2.12-5.68, p < 0.0001; MI: HR 2.1, 95% Cl 1.26-3.43, p = 0.0041). Rate of stroke/transient ischemic attack did not differ between groups. Discriminative potency to predict major and minor bleeding, MACCE, death and MI were high with nearly equal cut-off values calculated by Youden's index (YI) (major bleeding: Area under the curve [AUC] 0.66; p = 0.026; YI 32; minor bleeding: AUC 0.72; p = 0.001; YI 28; MACCE: AUC 0.62; p < 0.0001; YI 24)., Conclusion: In our cohort, PD score predicted bleeding moderately in post-PCI patients. In this study, ischemic events were predicted as well. Adaption of antiplatelet therapy duration by PD score is accurate. Nevertheless, it should be well-balanced with patient-related risk for ischemic events., Competing Interests: The authors declared that there is no conflict of interest., (© 2021 Published by Elsevier B.V.)

Purpose: ACE inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are important drugs in cardiovascular disease. However, little is known about which of these drug class is to be preferred. First analyses show that the blockade of the renin-angiotensin-aldosterone system (RAAS) influences platelet reactivity. Therefore, we evaluated the effects of ACEI and ARB on platelet reactivity and thrombin generation., Methods: We conducted a time series analysis in 34 patients. We performed light transmission aggregometry (LTA) to evaluate platelet reactivity. Results are given as maximum of aggregation (MoA). Thrombin generation was measured as endogenous thrombin potential (ETP) via calibrated automated thrombogram. Flow cytometry was used to analyze protease-activated receptor (PAR)-1 expression., Results: ACEI treatment significantly increased platelet reactivity already 4 h after initiation of treatment (prior vs. 4 h post ACEI: MoA 41.9 ± 16.2% vs. 55.2 ± 16.7%; p = 0.003). After switching from ACEI to ARB treatment, platelet reactivity decreased significantly (3 months after switching: MoA 34.7 ± 20.9%; p = 0.03). ACEI reduced endogenous thrombin potential significantly from before to 3 months after ACEI (ETP 1527 ± 437 nM × min vs. 1088 ± 631 nM × min; p = 0.025). Platelet thrombin receptor (PAR1) expression increased from 37.38 ± 10.97% before to 49.53 ± 6.04% after ACEI treatment (p = 0.036)., Conclusion: ACEI enhanced platelet reactivity. This can be reversed by changing to ARB. The mechanism behind RAAS influencing platelet function seems to be associated with PAR-1 expression.

Rationale: A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation treated with FXa (factor Xa) inhibitors including rivaroxaban compared with vitamin K antagonists. At the same time, low-dose rivaroxaban has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease. Yet, the mechanisms underlying this reduction remain unknown., Objective: In this study, we hypothesized that rivaroxaban's antithrombotic potential is linked to a hitherto unknown rivaroxaban effect that impacts on platelet reactivity and arterial thrombosis., Methods and Results: In this study, we identified FXa as potent, direct agonist of the PAR-1 (protease-activated receptor 1), leading to platelet activation and thrombus formation, which can be inhibited by rivaroxaban. We found that rivaroxaban reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillation patients on permanent rivaroxaban treatment for stroke prevention, respective controls, and patients with new-onset atrial fibrillation before and after first intake of rivaroxaban (time series analysis) were recruited. Platelet aggregation responses, as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material, were attenuated by rivaroxaban. We show that rivaroxaban's antiplatelet effect is plasma dependent but independent of thrombin and rivaroxaban's anticoagulatory capacity., Conclusions: Here, we identified FXa as potent platelet agonist that acts through PAR-1. Therefore, rivaroxaban exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.