New categorization of chest pain: noncardiac is in, atypical is out!

Chest pain poses a diagnostic challenge in the emergency department and requires a thorough clinical assessment. The traditional distinction between "atypical" and "typical" chest pain carries the risk of not addressing nonischemic clinical pictures. The newly conceived subdivision into cardiac, possibly cardiac, and (probably) noncardiac causes of the presenting symptom complex addresses a much more interdisciplinary approach to a symptom-oriented diagnostic algorithm. The diagnostic structures of the chest pain units in Germany do not currently reflect this. An adaptation should therefore be considered.

Clinical analysis on diagnostic accuracy of Bosch Vivalytic SARS-CoV-2 point-of-care test and evaluation of cycle threshold at admission for COVID-19 risk assessment.

BACKGROUND: Point-of-care (POC) polymerase chain reaction (PCR) tests have the ability to improve testing efficiency in the Coronavirus disease 2019 (COVID-19) pandemic. However, real-world data on POC tests is scarce. OBJECTIVE: To evaluate the efficiency of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) POC test in a clinical setting and examine the prognostic value of cycle threshold (CT) on admission on the length of hospital stay (LOS) in COVID-19 patients. METHODS: Patients hospitalised between January and May 2021 were included in this prospective cohort study. Patients' nasopharyngeal swabs were tested for SARS-CoV-2 with Allplex™2019-nCoV (Seegene Inc.) real-time (RT) PCR assay as gold standard as well as a novel POC test (Bosch Vivalytic SARS-CoV-2 [Bosch]) and the SARS-CoV-2 Rapid Antigen Test (Roche) accordingly. Clinical sensitivity and specificity as well as inter- and intra-assay variability were analyzed. RESULTS: 120 patients met the inclusion criteria with 46 (38%) having a definite COVID-19 diagnosis by RT-PCR. Bosch Vivalytic SARS-CoV-2 POC had a sensitivity of 88% and specificity of 96%. The inter- and intra- assay variability was below 15%. The CT value at baseline was lower in patients with LOS ≥ 10 days when compared to patients with LOS < 10 days (27.82 (± 4.648) vs. 36.2 (25.9-39.18); p = 0.0191). There was a negative correlation of CT at admission and LOS (r[44]s = - 0.31; p = 0.038) but only age was associated with the probability of an increased LOS in a multiple logistic regression analysis (OR 1.105 [95% CI, 1.03-1.19]; p = 0.006). CONCLUSION: Our data indicate that POC testing with Bosch Vivalytic SARS-CoV-2 is a valid strategy to identify COVID-19 patients and decrease turnaround time to definite COVID-19 diagnosis. Also, our data suggest that age at admission possibly with CT value as a combined parameter could be a promising tool for risk assessment of increased length of hospital stay and severity of disease in COVID-19 patients.

Medical history of coronary artery disease and time to electrocardiogram in the emergency department: a real-life, single-center, retrospective analysis.

BACKGROUND: Timely acquisition of 12-lead Electrocardiogram (ECG) in the emergency department (ED) is crucial and recommended by current guidelines. OBJECTIVES: To evaluate the association of medical history of coronary artery disease (hCAD) on door-to-ECG time in the ED. METHODS: In this single center, retrospective cohort study, patients admitted to ED for cardiac evaluation were grouped according to hCAD and no hCAD. The primary outcome was door-to-ECG time. A multivariate analysis adjusted for the cofounders sex, age, type of referral and shift was performed to evaluate the association of hCAD with door-to-ECG time. RESULTS: 1101 patients were included in this analysis. 362 patients (33%) had hCAD. Patients with hCAD had shorter door-to-ECG time (20 min. [Inter Quartile Range [IQR] 13-30] vs. 22 min. [IQR 14-37]; p < 0.001) when compared to patients with no hCAD. In a multivariable regression analysis hCAD was significantly associated with a shorter door-to-ECG time (- 3 min [p = 0.007; 95% confidence Interval [CI] - 5.16 to - 0.84 min]). CONCLUSION: In this single center registry, hCAD was associated with shorter door-to-ECG time. In patients presenting in ED for cardiac evaluation, timely ECG diagnostic should be facilitated irrespective of hCAD.

Platelet Serotonin Aggravates Myocardial Ischemia/Reperfusion Injury via Neutrophil Degranulation.

BACKGROUND: Platelets store large amounts of serotonin that they release during thrombus formation or acute inflammation. This facilitates hemostasis and modulates the inflammatory response. METHODS: Infarct size, heart function, and inflammatory cell composition were analyzed in mouse models of myocardial reperfusion injury with genetic and pharmacological depletion of platelet serotonin. These studies were complemented by in vitro serotonin stimulation assays of platelets and leukocytes in mice and men, and by measuring plasma serotonin levels and leukocyte activation in patients with acute coronary syndrome. RESULTS: Platelet-derived serotonin induced neutrophil degranulation with release of myeloperoxidase and hydrogen peroxide (H2O2) and increased expression of membrane-bound leukocyte adhesion molecule CD11b, leading to enhanced inflammation in the infarct area and reduced myocardial salvage. In patients hospitalized with acute coronary syndrome, plasmatic serotonin levels correlated with CD11b expression on neutrophils and myeloperoxidase plasma levels. Long-term serotonin reuptake inhibition-reported to protect patients with depression from cardiovascular events-resulted in the depletion of platelet serotonin stores in mice. These mice displayed a reduction in neutrophil degranulation and preserved cardiac function. In line, patients with depression using serotonin reuptake inhibition, presented with suppressed levels of CD11b surface expression on neutrophils and lower myeloperoxidase levels in blood. CONCLUSIONS: Taken together, we identify serotonin as a potent therapeutic target in neutrophil-dependent thromboinflammation during myocardial reperfusion injury.

Cardiac arrhythmias in the emergency settings of acute coronary syndrome and revascularization: an European Heart Rhythm Association (EHRA) consensus document, endorsed by the European Association of Percutaneous Cardiovascular Interventions (EAPCI), and European Acute Cardiovascular Care Association (ACCA).

Despite major therapeutic advances over the last decades, complex supraventricular and ventricular arrhythmias (VAs), particularly in the emergency setting or during revascularization for acute myocardial infarction (AMI), remain an important clinical problem. Although the incidence of VAs has declined in the hospital phase of acute coronary syndromes (ACS), mainly due to prompt revascularization and optimal medical therapy, still up to 6% patients with ACS develop ventricular tachycardia and/or ventricular fibrillation within the first hours of ACS symptoms. Despite sustained VAs being perceived predictors of worse in-hospital outcomes, specific associations between the type of VAs, arrhythmia timing, applied treatment strategies and long-term prognosis in AMI are vague. Atrial fibrillation (AF) is the most common supraventricular tachyarrhythmia that may be asymptomatic and/or may be associated with rapid haemodynamic deterioration requiring immediate treatment. It is estimated that over 20% AMI patients may have a history of AF, whereas the new-onset arrhythmia may occur in 5% patients with ST elevation myocardial infarction. Importantly, patients who were treated with primary percutaneous coronary intervention for AMI and developed AF have higher rates of adverse events and mortality compared with subjects free of arrhythmia. The scope of this position document is to cover the clinical implications and pharmacological/non-pharmacological management of arrhythmias in emergency presentations and during revascularization. Current evidence for clinical relevance of specific types of VAs complicating AMI in relation to arrhythmia timing has been discussed.

Expression of the oxygen-sensitive transcription factor subunit HIF-1α in patients suffering from secondary Raynaud syndrome.

Anti-ischemic therapy remains a challenge due to the complexity of hypoxia response pathways. Hypoxia-inducible factor (HIF)-1 is a heterodimer transcription factor consisting of 2 subunits, HIF-1α and HIF-1ß. Hypoxia-dependent activation of HIF-1α regulates cellular O2 homeostasis. Raynaud syndrome (RS), as a comorbidity of the autoimmune disease systemic sclerosis (SS), is characterized by vasospasms that limit blood flow to the limbs, resulting in hypoxia. A single-center randomized study was conducted to compare prostaglandin E1 (PgE1) therapy with a treatment combining PgE1 and an endothelin-1 blocker, bosentan. A total of 30 patients suffering from SS with RS were enrolled. We examined the regulation of HIF-1α, its target heme oxygenase-1 (HMOX-1), and the serum levels of the HIF-1α protein in a subset of patients as well as in ten healthy individuals. The expression of HIF-1α and HMOX-1 in monocytes was measured using absolute plasmid-based quantitative real-time PCR, whereas serum HIF-1α levels were measured with ELISA. Samples were taken at the time of randomization and after 24 weeks. We found that HIF-1α and HMOX-1 mRNA expression in monocytes and serum HIF-1α protein levels were significantly higher in the SS/RS patients compared to the healthy control group. Single-drug therapy significantly increased HIF-1α and HMOX-1 mRNA expression in monocytes and serum HIF-1α protein levels in the SS/RS patients compared to those at the time of randomization, whereas combining PgE1 with an endothelin-1 blocker prevented the further increases in HIF-1α and HMOX-1 expression. We propose HIF-1α and HMOX-1 as novel markers for anti-ischemic therapy in RS.

Extracellular HtrA2 Induces Apoptosis in Human Umbilical Vein Endothelial Cells.

The serine protease high-temperature-required protein A2 (HtrA2) has been identified as a key intracellular molecule promoting apoptosis in cells during ischemia reperfusion (IR) injury. IR injury in ST-segment elevation myocardial infarction (STEMI) contributes to overall myocardial damage. HtrA2 has further been shown to be significantly increased in the serum of patients with STEMI. In the present pilot study, we use human umbilical vein endothelial cells (HUVECs) to investigate whether extracellular HtrA2 induces apoptosis using Annexin V staining. Furthermore, we examine whether HtrA2 is released extracellularly after staurosporine-induced apoptosis using ELISA. We find that HtrA2 is released upon induction of apoptosis by staurosporine into the cell culture medium. Furthermore, treatment of HUVECs with extracellular HtrA2-induces apoptosis, while the addition of anti-HtrA2 antibodies reduces both HtrA2- and staurosporine-induced endothelial cell apoptosis. In conclusion, we show here that extracellular HtrA2 induces apoptosis in human endothelial cells, although the exact molecular mechanisms have to be investigated in future.

Chip-based digital PCR as a novel detection method for quantifying microRNAs in acute myocardial infarction patients.

miRNAs have shown promise as potential biomarkers for acute myocardial infarction (AMI). However, the current used quantitative real-time PCR (qRT-PCR) allows solely for relative expression of nucleic acids and it is susceptible to day-to-day variability, which has limited the validity of using the miRNAs as biomarkers. In this study we explored the technical qualities and diagnostic potential of a new technique, chip-based digital PCR, in quantifying the miRNAs in patients with AMI and ischaemia-reperfusion injury (I/R). In a dilution series of synthetic C.elegans-miR-39, chip-based digital PCR displayed a lower coefficient of variation (8.9% vs 46.3%) and a lower limit of detection (0.2 copies/µL vs 1.1 copies/µL) compared with qRT-PCR. In the serum collected from 24 patients with ST-elevation myocardial infarction (STEMI) and 20 patients with stable coronary artery disease (CAD) patients after percutaneous coronary intervention (PCI), we used qRT-PCR and multiplexed chip-based digital PCR to quantify the serum levels of miRNA-21 and miRNA-499 as they have been validated in AMI in prior studies. In STEMI, I/R injury was assessed via measurement of ST-segment resolution (ST-R). Chip-based digital PCR revealed a statistical significance in the difference of miR-21 levels between stable CAD and STEMI groups (118.8 copies/µL vs 59 copies/µL; P=0.0300), whereas qRT-PCR was unable to reach significance (136.4 copies/µL vs 122.8 copies/µL; P=0.2273). For miR-499 levels, both chip-based digital PCR and qRT-PCR revealed statistically significant differences between stable CAD and STEMI groups (2 copies/µL vs 8.5 copies/µL, P=0.0011; 0 copies/µL vs 19.4 copies/µL; P<0.0001). There was no association between miR-21/499 levels and ST-R post-PCI. Our results show that the chip-based digital PCR exhibits superior technical qualities and promises to be a superior method for quantifying miRNA levels in the circulation, which may become a more accurate and reproducible method for directly quantifying miRNAs, particularly for use in large multi-centre clinical trials.

Aortic root volume is associated with contained rupture of the aortic annulus in balloon-expandable transcatheter aortic valve replacement.

BACKGROUND: Aortic annulus rupture is a rare, but potentially fatal complication of transcatheter aortic valve replacement (TAVR), especially when it occurs by balloon-expandable devices. In order to improve the predictability of procedures and avoid ruptures we investigated whether or not the aortic root volume measures is a useful indicator of risk, and if it could be useful for the prosthesis size selection. METHODS AND RESULTS: From a retrospective series of 172 TAVR patients, seven experienced contained aortic annulus ruptures. The receiver operating curves were used to illustrate sensitivity and specificity of the different aortic annulus size and aortic root volume measures. The annulus area oversizing of ≥20% resulted in a sensitivity of 100%, specificity of 55.76%, and positive predictive value (PPV) of 8.75%. In patients receiving 26 mm prostheses, the aortic root volume (ARV <13600 mm(3)) provided a better specificity and PPV (79.63 and 18.52%, respectively). A two-step testing procedure considering the area derived average annulus diameter (Darea <23 mm) as a first separating parameter and then the ARV (<13,600 mm(3)) as a further indicator showed the most promising results with the PPV of 31.25%. Regardless of the procedure steps no false negative results were predicted. CONCLUSIONS: Our data show that the ARV provides a better predictive value for correct prosthesis sizing than established annulus measurements, especially in 'borderline' annuli. We suggest a two-step testing procedure for prostheses size selection, considering Darea and ARV to minimize the risk of annulus rupture. Prospective studies and examination of larger datasets are warranted to confirm these findings.

Towards effective and safe thrombolysis and thromboprophylaxis: preclinical testing of a novel antibody-targeted recombinant plasminogen activator directed against activated platelets.

RATIONALE: Fibrinolysis is a valuable alternative for the treatment of myocardial infarction when percutaneous coronary intervention is not available in a timely fashion. For acute ischemic stroke, fibrinolysis is the only treatment option with a very narrow therapeutic window. Clinically approved thrombolytics have significant drawbacks, including bleeding complications. Thus their use is highly restricted, leaving many patients untreated. OBJECTIVE: We developed a novel targeted fibrinolytic drug that is directed against activated platelets. METHODS AND RESULTS: We fused single-chain urokinase plasminogen activator (scuPA) to a small recombinant antibody (scFvSCE5), which targets the activated form of the platelet-integrin glycoprotein IIb/IIIa. Antibody binding and scuPA activity of this recombinant fusion protein were on par with the parent molecules. Prophylactic in vivo administration of scFvSCE5-scuPA (75 U/g body weight) prevented carotid artery occlusion after ferric chloride injury in a plasminogen-dependent process compared with saline (P<0.001), and blood flow recovery was similar to high-dose nontargeted urokinase (500 U/g body weight). Tail bleeding time was significantly prolonged with this high dose of nontargeted urokinase, but not with equally effective targeted scFvSCE5-scuPA at 75 U/g body weight. Real-time in vivo molecular ultrasound imaging demonstrates significant therapeutic reduction of thrombus size after administration of 75 U/g body weight scFvSCE5-scuPA as compared with the same dose of a mutated, nontargeting scFv-scuPA or vehicle. The ability of scFvSCE5-scuPA to lyse thrombi was lost in plasminogen-deficient mice, but could be restored by intravenous injection of plasminogen. CONCLUSIONS: Targeting of scuPA to activated glycoprotein IIb/IIIa allows effective thrombolysis and the potential novel use as a fibrinolytic agent for thromboprophylaxis without bleeding complications.

Dual pathway therapy in acute coronary syndrome.

In 10 % of patients, who suffer an acute coronary syndrome (ACS), a major cardiovascular event occurs despite optimal therapy. The occlusion of the vessel is driven by atherothrombosis, which arises from platelet activation and activation of the coagulation cascade. In the last decade the secondary prevention continuously improved by development of dual anti-platelet therapy with new P2Y12-inhibitors such as clopidogrel, prasugrel, and ticagrelor. Until recently, the coagulation cascade was not targeted in secondary prevention. The coagulation factor Xa plays a crucial role in thrombosis and is elevated in patients after acute coronary syndrome, therefore representing an attractive target for novel therapies in ACS. Former studies with vitamin K antagonists showed reduction of cardiovascular events but increased major bleedings. Two phase-3 trials investigated the role of novel oral anticoagulant agents on top of aspirin and clopidogrel in patients with ACS. The APPRAISE-2 study, which tested the oral factor Xa inhibitor apixaban was prematurely terminated because of an increase of major bleedings in the absence of an effect on cardiovascular events. In contrast, the ATLAS ACS2 TIMI-51 trial interrogating the oral factor Xa inhibitor rivaroxaban in a low dose regimen showed significant reduction of cardiovascular events as well as total mortality. Thus, add-on treatment with low dose rivaroxaban emerged as a new option for patients with ACS. This review illustrates recent advances in the development of antithrombotic therapy in acute coronary syndromes, provides guidance on which patients should receive which therapy for secondary prevention of events, and points out potentially fruitful new strategies for the future of antithrombotic treatment in ACS.

Protective role for Toll-like receptor-9 in the development of atherosclerosis in apolipoprotein E-deficient mice.

OBJECTIVE: Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9 has a role in the development of atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice. APPROACH AND RESULTS: Newly generated double-knockout ApoE(-/-):TLR9(-/-) mice and control ApoE(-/-) mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE(-/-):TLR9(-/-) mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4(+) T cells. Although ApoE(-/-):TLR9(-/-) mice exhibited an increase in plasma very low-density lipoprotein/low-density-lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE(-/-):TLR9(-/-) mice, CD4(+) T-cell accumulation was further investigated and depletion of these cells in ApoE(-/-):TLR9(-/-) mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9 agonist (type B CpG oligodeoxynucleotide 1668) to ApoE(-/-) mice resulted in a reduction of lesion severity. CONCLUSIONS: Genetic deletion of the innate immune receptor TLR9 exacerbated atherosclerosis in ApoE(-/-) mice fed a high-fat diet. CD4(+) T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9 agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis.

Novel single-chain antibody-targeted microbubbles for molecular ultrasound imaging of thrombosis: validation of a unique noninvasive method for rapid and sensitive detection of thrombi and monitoring of success or failure of thrombolysis in mice.

BACKGROUND: Molecular imaging is a fast emerging technology allowing noninvasive detection of vascular pathologies. However, imaging modalities offering high resolution currently do not allow real-time imaging. We hypothesized that contrast-enhanced ultrasound with microbubbles (MBs) selectively targeted to activated platelets would offer high-resolution, real-time molecular imaging of evolving and dissolving arterial thrombi. METHODS AND RESULTS: Lipid-shell based gas-filled MBs were conjugated to either a single-chain antibody specific for activated glycoprotein IIb/IIIa via binding to a Ligand-Induced Binding Site (LIBS-MBs) or a nonspecific single-chain antibody (control MBs). Successful conjugation was assessed in flow cytometry and immunofluorescence double staining. LIBS-MBs but not control MBs strongly adhered to both immobilized activated platelets and microthrombi under flow. Thrombi induced in carotid arteries of C57Bl6 mice in vivo by ferric chloride injury were then assessed with ultrasound before and 20 minutes after MB injection through the use of gray-scale area intensity measurement. Gray-scale units converted to decibels demonstrated a significant increase after LIBS-MB but not after control MB injection (9.55±1.7 versus 1.46±1.3 dB; P<0.01). Furthermore, after thrombolysis with urokinase, LIBS-MB ultrasound imaging allows monitoring of the reduction of thrombus size (P<0.001). CONCLUSION: We demonstrate that glycoprotein IIb/IIIa-targeted MBs specifically bind to activated platelets in vitro and allow real-time molecular imaging of acute arterial thrombosis and monitoring of the success or failure of pharmacological thrombolysis in vivo.

Pulmonary embolism response team (PERT) implementation and its clinical value across countries: a scoping review and meta-analysis.

BACKGROUND: Over the last years, multidisciplinary pulmonary embolism response teams (PERTs) have emerged to encounter the increasing variety and complexity in the management of acute pulmonary embolism (PE). We aimed to systematically investigate the composition and added clinical value of PERTs. METHODS: We searched PubMed, CENTRAL and Web of Science until January 2022 for articles designed to describe the structure and function of PERTs. We performed a random-effects meta-analysis of controlled studies (PERT vs. pre-PERT era) to investigate the impact of PERTs on clinical outcomes and advanced therapies use. RESULTS: We included 22 original studies and four surveys. Overall, 31.5% of patients with PE were evaluated by PERT referred mostly by emergency departments (59.4%). In 11 single-arm studies (1532 intermediate-risk and high-risk patients evaluated by PERT) mortality rate was 10%, bleeding rate 9% and length of stay 7.3 days [95% confidence interval (CI) 5.7-8.9]. In nine controlled studies there was no difference in mortality [risk ratio (RR) 0.89, 95% CI 0.67-1.19] by comparing pre-PERT with PERT era. When analysing patients with intermediate or high-risk class only, the effect estimate for mortality tended to be lower for patients treated in the PERT era compared to those treated in the pre-PERT era (RR 0.71, 95% CI 0.45-1.12). The use of advanced therapies was higher (RR 2.67, 95% CI 1.29-5.50) and the in-hospital stay shorter (mean difference - 1.6 days) in PERT era compared to pre-PERT era. CONCLUSIONS: PERT implementation led to greater use of advanced therapies and shorter in-hospital stay. Our meta-analysis did not show a survival benefit in patients with PE since PERT implementation. Large prospective studies are needed to further explore the impact of PERTs on clinical outcomes. REGISTRATION: Open Science Framework 10.17605/OSF.IO/SBFK9.

A nationwide analysis of reperfusion therapies for pulmonary embolism in older patients with frailty.

BACKGROUND: Reperfusion therapy is challenging in the elderly. Catheter-directed therapies are an alternative for higher-risk pulmonary embolism (PE) patients if systemic thrombolysis (ST) is contraindicated or has failed. Their safety has not been evaluated in specific vulnerable populations. AIMS: We aimed to assess the safety of reperfusion therapies in elderly and frail patients in the real world. METHODS: In the US Nationwide Inpatient Sample from 2016 to 2020, we identified hospitalisations of patients ≥65 years with PE and defined a frailty subgroup using the Johns Hopkins Adjusted Clinical Groups frailty-defining diagnosis indicator. We investigated reperfusion therapies (ST, catheter-directed thrombolysis [CDT], catheter-based thrombectomy [CBT], surgical embolectomy [SE]) and their associated safety outcomes (overall and major bleeding). RESULTS: Among 980,245 hospitalisations of patients ≥65 years with PE (28.0% frail), reperfusion therapies were used in 4.9% (17.6% among high-risk PE). ST utilisation remained stable, while the use of catheter-directed therapies increased from 1.7% in 2016 to 3.2% in 2020. Among all hospitalisations with reperfusion, CDT, compared to ST, was associated with reduced major bleeding (5.8% vs 12.2%, odds ratio [OR] 0.58, 95% confidence interval [CI]: 0.49-0.70); these results also applied to frail patients. CBT, compared to SE, was also associated with reduced major bleeding (11.0% vs 22.4%, OR 0.63, 95% CI: 0.43-0.91), but not among frail patients. These differences were particularly significant in patients with non-high-risk PE. Differences persisted for overall bleeding as well. CONCLUSIONS: Catheter-directed therapies may be a safer alternative to classical reperfusion therapies for elderly and frail patients with PE requiring reperfusion treatment.

De-escalation or abbreviation of dual antiplatelet therapy in acute coronary syndromes and percutaneous coronary intervention: a Consensus Statement from an international expert panel on coronary thrombosis.

Conventional dual antiplatelet therapy (DAPT) for patients with acute coronary syndromes undergoing percutaneous coronary intervention comprises aspirin with a potent P2Y purinoceptor 12 (P2Y12) inhibitor (prasugrel or ticagrelor) for 12 months. Although this approach reduces ischaemic risk, patients are exposed to a substantial risk of bleeding. Strategies to reduce bleeding include de-escalation of DAPT intensity (downgrading from potent P2Y12 inhibitor at conventional doses to either clopidogrel or reduced-dose prasugrel) or abbreviation of DAPT duration. Either strategy requires assessment of the ischaemic and bleeding risks of each individual. De-escalation of DAPT intensity can reduce bleeding without increasing ischaemic events and can be guided by platelet function testing or genotyping. Abbreviation of DAPT duration after 1-6 months, followed by monotherapy with aspirin or a P2Y12 inhibitor, reduces bleeding without an increase in ischaemic events in patients at high bleeding risk, particularly those without high ischaemic risk. However, these two strategies have not yet been compared in a head-to-head clinical trial. In this Consensus Statement, we summarize the evidence base for these treatment approaches, provide guidance on the assessment of ischaemic and bleeding risks, and provide consensus statements from an international panel of experts to help clinicians to optimize these DAPT approaches for individual patients to improve outcomes.

Acute heart failure and valvular heart disease: A scientific statement of the Heart Failure Association, the Association for Acute CardioVascular Care and the European Association of Percutaneous Cardiovascular Interventions of the European Society of Cardiology.

Acute heart failure (AHF) represents a broad spectrum of disease states, resulting from the interaction between an acute precipitant and a patient's underlying cardiac substrate and comorbidities. Valvular heart disease (VHD) is frequently associated with AHF. AHF may result from several precipitants that add an acute haemodynamic stress superimposed on a chronic valvular lesion or may occur as a consequence of a new significant valvular lesion. Regardless of the mechanism, clinical presentation may vary from acute decompensated heart failure to cardiogenic shock. Assessing the severity of VHD as well as the correlation between VHD severity and symptoms may be difficult in patients with AHF because of the rapid variation in loading conditions, concomitant destabilization of the associated comorbidities and the presence of combined valvular lesions. Evidence-based interventions targeting VHD in settings of AHF have yet to be identified, as patients with severe VHD are often excluded from randomized trials in AHF, so results from these trials do not generalize to those with VHD. Furthermore, there are not rigorously conducted randomized controlled trials in the setting of VHD and AHF, most of the data coming from observational studies. Thus, distinct to chronic settings, current guidelines are very elusive when patients with severe VHD present with AHF, and a clear-cut strategy could not be yet defined. Given the paucity of evidence in this subset of AHF patients, the aim of this scientific statement is to describe the epidemiology, pathophysiology, and overall treatment approach for patients with VHD who present with AHF.

High-mobility group box protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein e-deficient mice.

OBJECTIVE: High-mobility group box protein 1 (HMGB1) is a DNA-binding protein and cytokine highly expressed in atherosclerotic lesions, but its pathophysiological role in atherosclerosis is unknown. We investigated its role in the development of atherosclerosis in ApoE-/- mice. METHODS AND RESULTS: Apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet were administered a monoclonal anti-HMGB1 neutralizing antibody, and the effects on lesion size, immune cell accumulation, and proinflammatory mediators were assessed using Oil Red O, immunohistochemistry, and real-time polymerase chain reaction. As with human atherosclerotic lesions, lesions in ApoE-/- mice expressed HMGB1. Treatment with the neutralizing antibody attenuated atherosclerosis by 55%. Macrophage accumulation was reduced by 43%, and vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 expression was attenuated by 48% and 72%, respectively. CD11c+ dendritic cells were reduced by 65%, and the mature (CD83+) population was reduced by 60%. Treatment also reduced CD4+ cells by nearly 50%. mRNAs in lesions encoding tumor necrosis factor-α and interleukin-1ß tended to be reduced. Mechanistically, HMGB1 stimulated macrophage migration in vitro and in vivo; in vivo, it markedly augmented the accumulation of F4/80+Gr-1(Ly-6C)+ macrophages and also increased F4/80+CD11b+ macrophage numbers. CONCLUSIONS: HMGB1 exerts proatherogenic effects augmenting lesion development by stimulating macrophage migration, modulating proinflammatory mediators, and encouraging the accumulation of immune and smooth muscle cells.

Healthcare resource utilization and costs of cardiovascular events in patients with atherosclerotic cardiovascular disease in Germany - results of a claims database study.

OBJECTIVES: We assessed healthcare resource utilization (HCRU) and costs of cardiovascular (CV) events in patients with a history of atherosclerotic cardiovascular disease (ASCVD) in Germany. METHODS: We conducted a retrospective matched case-control study based on German claims data from 1 January 2012 to 31 December 2017 using the "Institute for Applied Health Research Berlin" (InGef) Research Database. Cases who had a myocardial infarction (MI), stroke and angina pectoris identified by ICD-10-GM codes between 1 January 2014 and 31 December 2016 were matched to event-free controls by an exact matching approach without replacement at a ratio of 1:2. Costs and HCRU were assessed in individual 1-year follow-up periods after the index event for the overall cohort and subgroups of MI cases and stroke cases. RESULTS: The overall cohort consisted of a total of 14,169 cases with a CV index event matched to 28,338 controls. The mean age of the overall cohort was 73.3 years, 34.1% of the patients were female, 3,717 (26.2%) had an MI, and 3,752 (26.5%) had stroke. Following the index events, 12.2% of cases in the overall cohort, 12.6% of MI cases, and 8.7% of stroke cases experienced a recurrent CV event. CV cases had on average 1.7 more all-cause hospitalizations (p <0.001) and 6.1 more outpatient visits (p <0.001) during the 1-year follow-up period than did controls. In the MI and stroke subgroups, cases had on average 1.8 and 1.6 more all-cause hospitalizations and 7.0 and 4.0 more outpatient visits, respectively (differences were statistically significant). Compared to controls, cases incurred on average higher total healthcare costs: by €11,898 for overall cases, by €16,349 for MI, and by €14,360 in stroke cases (overall: p <0.001; MI: p <0.001; stroke: p <0.001). CONCLUSION: CV events in ASCVD patients pose a considerable clinical burden on patients and cause significant costs for the German statutory healthcare system.