Indications for an early invasive strategy in NSTE-ACS patients.

An early invasive strategy in patients who have acute coronary syndrome without ST-elevation (NSTE-ACS) can improve clinical outcome in high-risk subgroups. According to the current guidelines of the European Society of Cardiology (ESC), the majority of NSTE-ACS patients are classified as "high-risk". We propose to prioritise patients with a global registry of acute coronary events (GRACE) risk score >140 over patients with isolated troponin rise or electrocardiographic changes and a GRACE risk score <140. We also acknowledge that same-day transfer for all patients at a high risk is not necessary in the Netherlands since the majority of Dutch cardiology departments are equipped with a catheterisation laboratory where diagnostic coronary angiography is routinely performed in NSTE-ACS patients. Therefore, same-day transfer should be restricted to true high-risk patients (in addition to those NSTE-ACS patients with very high-risk (VHR) criteria) in centres without coronary angiography capabilities.

Reversibility of platelet P2Y12 inhibition by platelet supplementation: ex vivo and in vitro comparisons of prasugrel, clopidogrel and ticagrelor.

Essentials Successful outcome of platelet transfusion depends on specific antiplatelet therapy in use. We assessed if ticagrelor, clopidogrel or prasugrel impacts on donor platelet activity ex vivo. Ticagrelor and/or its active metabolite in plasma or bound to platelets can inhibit donor platelets. This might compromise the effectiveness of platelet transfusion therapy. SUMMARY: Background Platelet transfusion is the conventional approach to restore platelet function during acute bleeds or surgery, but successful outcome depends on the specific antiplatelet therapy. Notably ticagrelor is associated with inadequate recovery of platelet function after platelet transfusion. We examined whether plasma and/or platelets from ticagrelor-treated patients influence donor platelet function, in comparison with clopidogrel and prasugrel. Methods Platelet transfusion was mimicked ex vivo by mixing naïve donor platelet-rich plasma (PRP) or gel-filtered platelets (GFP) in defined proportions with PRP, plasma or GFP from cardiovascular patients receiving standard care including medication with prasugrel, clopidogrel or ticagrelor (n = 20 each). Blood was taken 4 h after the previous dose. HLA2/HLA28 haplotyping let us distinguish net (all platelet) and individual patient/donor platelet reactivity in mixtures of patient/donor platelets, measured by flow cytometry analysis of ADP-induced fibrinogen binding and CD62P expression. Results ADP responsiveness of donor platelets was dramatically reduced by even low (10%) concentrations of PRP or plasma from ticagrelor-treated patients. Clopidogrel and prasugrel were associated with more modest donor platelet inhibition. GFP from ticagrelor-treated patients but not patients receiving clopidogrel or prasugrel also suppressed donor GFP function upon mixing, suggesting the transfer of ticagrelor from patient platelets to donor platelets. This transfer did not lead to recovery of ADP responsiveness of patient's platelets. Conclusion Collectively, these observations support the concept that ticagrelor and/or its active metabolite in plasma or bound to platelets can inhibit donor platelets, which might compromise the effectiveness of platelet transfusion therapy.

Monocyte gene expression in childhood obesity is associated with obesity and complexity of atherosclerosis in adults.

Childhood obesity coincides with increased numbers of circulating classical CD14++CD16- and intermediate CD14++CD16+ monocytes. Monocytes are key players in the development and exacerbation of atherosclerosis, which prompts the question as to whether the monocytosis in childhood obesity contributes to atherogenesis over the years. Here, we dissected the monocyte gene expression profile in childhood obesity using an Illumina microarray platform on sorted monocytes of 35 obese children and 16 lean controls. Obese children displayed a distinctive monocyte gene expression profile compared to lean controls. Upon validation with quantitative PCR, we studied the association of the top 5 differentially regulated monocyte genes in childhood obesity with obesity and complexity of coronary atherosclerosis (SYNTAX score) in a cohort of 351 adults at risk for ischemic cardiovascular disease. The downregulation of monocyte IMPDH2 and TMEM134 in childhood obesity was also observed in obese adults. Moreover, downregulation of monocyte TMEM134 was associated with a higher SYNTAX atherosclerosis score in adults. In conclusion, childhood obesity entails monocyte gene expression alterations associated with obesity and enhanced complexity of coronary atherosclerosis in adults.

Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention or after acute coronary syndrome : Practical lessons from a review.

To prevent recurrent ischaemic events, dual antiplatelet therapy (DAPT) is the standard of care after percutaneous coronary intervention and in the treatment of acute coronary syndrome. Recent evidence supports an adjusted DAPT duration in selected patients.The current paper aims to encourage cardiologists to actively search for patients benefiting from either shorter or prolonged duration DAPT and proposes an algorithm to identify patients who are likely to benefit from such an alternative strategy.Individualised DAPT duration should be considered in high-risk anatomic and/or clinical subgroups or in patients at increased haemorrhagic risk with low ischaemic risk. Both thrombotic and haemorrhagic risk should be assessed in all patients. In patients undergoing percutaneous coronary intervention, the interventional cardiologist could advise on the minimal duration of DAPT. However, in contrast to the minimum duration of DAPT for stent thrombosis prevention, longer duration DAPT is aimed at prevention of spontaneous myocardial infarction, and not at stent thrombosis, and thus the key to success is to treat the patient's overall thrombotic risk.The advice on the duration of DAPT must be documented in the patient's records and communicated with the treating physician and general practitioner. DAPT duration should be reassessed at least on a yearly basis.

On- versus off-hour care for patients with non-ST-segment elevation myocardial infarction in Germany : Exemplary results within the chest pain unit concept.

AIM: The aim of this study was to analyze differences in the timing of invasive management of patients with high-risk acute coronary syndrome without persistent ST-segment elevation (hr-NSTE-ACS) or myocardial infarction without persistent ST-segment elevation (NSTEMI) between on- and off-hours in a German chest pain unit (CPU). PATIENTS AND METHODS: We retrospectively enrolled 160 NSTEMI patients in the study, who were admitted to two German CPUs in 2013. Patients presenting on weekdays between 8 a.m. and 6 p.m. were compared with patients presenting during off-hours. Data analysis included time intervals from admission to invasive management (goals: for hr-NSTE-ACS, <2 h; for NSTEMI, <24 h) and the resulting guideline adherence. RESULTS: Guideline-adherent timing of an invasive strategy did not differ significantly between the on-hour (6.5 h [3.0-22.0 h], 79.9 %) and off-hour groups (10.5 h [2.0-20.0 h], 75.3 %; p = 0.94), without additional significant differences between admissions during off-hours Monday to Thursday and weekends (10.0 h [2.0-19.0 h], 75.6 % vs. 7.5 h [2.0-20.0 h], 76.2 %; p = 0.96). CONCLUSION: Our exemplary experience in two different German CPUs demonstrates adequate timing of coronary catheterization in over 75 % of cases, irrespective of admission during on- or off-hours. Nationwide validation of our findings by the German CPU registry is mandatory.

Cardiac shockwave therapy in patients with chronic refractory angina pectoris.

BACKGROUND: Cardiac shockwave therapy (CSWT) might improve symptoms and decrease ischaemia burden by stimulating collateral growth in chronic ischaemic myocardium. This prospective study was performed to evaluate the feasibility and safety of CSWT. METHODS: We included 33 patients (mean age 70 ± 7 years, mean left ventricular ejection fraction 55 ± 12 %) with end-stage coronary artery disease, chronic angina pectoris and reversible ischaemia on myocardial scintigraphy. CSWT was applied to the ischaemic zones (3-7 spots/session, 100 impulses/spot, 0.09 mJ/mm(2)) in an echocardiography-guided and ECG-triggered fashion. The protocol included a total of 9 treatment sessions (3 treatment sessions within 1 week at baseline, and after 1 and 2 months). Clinical assessment was performed using exercise testing, angina score (CCS class), nitrate use, myocardial scintigraphy, and cardiac magnetic resonance (CMR) 1 and 4 months after the last treatment session. RESULTS: One and 4 months after CSWT, sublingual nitrate use decreased from 10/week to 2/week (p < 0.01) and the angina symptoms diminished from CCS class III to CCS class II (p < 0.01). This clinical improvement was accompanied by an improved myocardial uptake on stress myocardial scintigraphy (54.2 ± 7.7 % to 56.4 ± 9.4 %, p = 0.016) and by increased exercise tolerance at 4-month follow-up (from 7.4 ± 2.8 to 8.8 ± 3.6 min p = 0.015). No clinically relevant side effects were observed. CONCLUSION: CSWT improved symptoms and reduced ischaemia burden in patients with end-stage coronary artery disease without relevant side effects. The study provides a solid basis for a randomised multicentre trial to establish CSWT as a new treatment option in end-stage coronary artery disease.

Treatment variation in stent choice in patients with stable or unstable coronary artery disease.

AIM: Variations in treatment are the result of differences in demographic and clinical factors (e.g. anatomy), but physician and hospital factors may also contribute to treatment variation. The choice of treatment is considered important since it could lead to differences in long-term outcomes. This study explores the associations with stent choice: i.e. drug-eluting stent (DES) versus bare-metal stents (BMS) for Dutch patients diagnosed with stable or unstable coronary artery disease (CAD). METHODS & RESULTS: Associations with treatment decisions were based on a prospective cohort of 692 patients with stable or unstable CAD. Of those patients, 442 patients were treated with BMS or DES. Multiple logistic regression analyses were performed to identify variables associated with stent choice. Bivariate analyses showed that NYHA class, number of diseased vessels, previous percutaneous coronary intervention, smoking, diabetes, and the treating hospital were associated with stent type. After correcting for other associations the treating hospital remained significantly associated with stent type in the stable CAD population. CONCLUSIONS: This study showed that several factors were associated with stent choice. While patients generally appear to receive the most optimal stent given their clinical characteristics, stent choice seems partially determined by the treating hospital, which may lead to differences in long-term outcomes.

Guideline-conforming timing of invasive management in troponin-positive or high-risk ACS without persistent ST-segment elevation in German chest pain units. Urban university maximum care vs. rural regional primary care.

AIM: This study aimed to analyze guideline adherence in the timing of invasive management for myocardial infarction without persistent ST-segment elevation (NSTEMI) in two exemplary German centers, comparing an urban university maximum care facility and a rural regional primary care facility. METHODS: All patients diagnosed as having NSTEMI during 2013 were retrospectively enrolled in two centers: (1) site I, a maximum care center in an urban university setting, and (b) site II, a primary care center in a rural regional care setting. Data acquisition included time intervals from admission to invasive management, risk criteria, rate of intervention, and medical therapy. RESULTS: The median time from admission to coronary angiography was 12.0 h (site I) or 17.5 h (site II; p = 0.17). Guideline-adherent timing was achieved in 88.1 % (site I) or 82.9 % (site II; p = 0.18) of cases. Intervention rates were high in both sites (site I-75.5 % vs. site II-75.3 %; p = 0.85). Adherence to recommendations of medical therapy was high and comparable between the two sites. CONCLUSION: In NSTEMI or high-risk acute coronary syndromes without persistent ST-segment elevation, guideline-adherent timing of invasive management was achieved in about 85 % of cases, and was comparable between urban maximum and rural primary care settings. Validation by the German Chest Pain Unit Registry including outcome analysis is required.

Right ventricular function in dilated cardiomyopathy and ischemic heart disease: assessment with non-invasive imaging.

BACKGROUND: Dilated cardiomyopathy and ischaemic heart disease can both lead to right ventricular (RV) dysfunction. Direct comparisons of the two entities regarding RV size and function using state-of-the-art imaging techniques have not yet been performed. We aimed to determine RV function and volume in dilated cardiomyopathy and ischaemic heart disease in relation to left ventricular (LV) systolic and diastolic function and systolic pulmonary artery pressure. METHODS AND RESULTS: A well-characterised group (cardiac magnetic resonance imaging, echocardiography, coronary angiography and endomyocardial biopsy) of 46 patients with dilated cardiomyopathy was compared with LV ejection fraction (EF)-matched patients (n = 23) with ischaemic heart disease. Volumes and EF were determined with magnetic resonance imaging, diastolic LV function and pulmonary artery pressure with echocardiography. After multivariable linear regression, four factors independently influenced RVEF (R(2) = 0.51, p < 0.001): LVEF (r = 0.54, p < 0.001), ratio of peak early and peak atrial transmitral Doppler flow velocity as measure of LV filling pressure (r = - 0.52, p < 0.001) and tricuspid regurgitation flow velocity as measure of pulmonary artery pressure (r = - 0.38, p = 0.001). RVEF was significantly worse in patients with dilated cardiomyopathy compared with ischaemic heart disease: median 48 % (interquartile range (IQR) 37-55 %) versus 56 % (IQR 48-63 %), p < 0.05. CONCLUSIONS: In patients with dilated cardiomyopathy and ischaemic heart disease, RV function is determined by LV systolic and diastolic function, the underlying cause of LV dysfunction, and pulmonary artery pressure. It was demonstrated that RV function is more impaired in dilated cardiomyopathy.

[Clinical practice of systemic lysis in prehospital resuscitation. Success and complication rates]. / Klinische Praxis der systemischen Lyse unter prähospitaler Reanimation. Erfolgs- und Komplikationsraten.

BACKGROUND: Systemic thrombolysis was introduced as the sole prehospital treatment option in patients with cardiac arrest in the setting of acute myocardial ischemia or pulmonary embolism; however, it remains the subject of discussion. PATIENTS AND METHODS: A total of 194 patients with sudden prehospital cardiac arrest were included in this retrospective case control study. Of these patients, 96 in whom circulatory arrest due to cardiac disease (pulmonary artery embolism or myocardial ischemia) was suspected underwent thrombolytic treatment and were compared to the remaining 98 patients that did not undergo thrombolytic therapy. In addition to the circumstances of circulatory arrest, the course and success of resuscitation, as well as in-hospital course (including bleeding complications), overall survival and neurological outcomes were compared. RESULTS: There were no significant differences between patients with or without thrombolysis in terms of the circumstances of cardiac arrest. Patients that received thrombolytic treatment were significantly younger and were more frequently treated with anticoagulants, platelet aggregation inhibitors and amiodarone. They also received higher doses of epinephrine and arrived at hospital under ongoing resuscitation significantly more frequently. A trend toward more prehospital return of spontaneous circulation (ROSC) following thrombolytic treatment was seen in the entire cohort. However, patients pre-treated with acetylsalicylic acid and heparin did not show better prehospital ROSC rates as a result of additional thrombolytic therapy. Significant differences in terms of bleeding complications or the need for blood transfusion could not be seen due to the small number of patients. DISCUSSION: The indication for systemic thrombolysis in the context of prehospital resuscitation should remain restricted to patients with clear symptoms of acute pulmonary embolism or recurrent episodes of ventricular fibrillation in the setting of acute myocardial infarction. Due to a lack of evidence, systemic thrombolysis should not be used as a treatment of last resort in younger patients with persistent ventricular fibrillation.

Infective endocarditis on ICU: risk factors, outcome and long-term follow-up.

OBJECTIVE: To identify factors associated with short-term, intermediate and long-term outcome in patients with infective endocarditis (IE) and the need for treatment on intensive care unit (ICU). DESIGN AND SETTING: Retrospective analysis and long-term follow-up by questionnaire in the two medical ICUs of our university hospital. PATIENTS: We conducted a retrospective analysis of all consecutive patients with IE and need for ICU treatment in our department between 2002 and 2009. All patients fulfilled the modified Duke criteria for definite diagnosis of IE. MEASUREMENTS AND MAIN RESULTS: Data of 216 patients (aged 62 ± 14 years, 31 % female) were analyzed, 15.7 % of whom had prosthetic valve endocarditis. Infectious agent (IA) was identified in 74 % and surgery was performed in 57 %. 56 patients (24.9 %) died on ICU, 9 patients were sent to palliative care units and died several days later. During follow-up, another 44 patients died. Multivariate Cox-regression analysis identified the following independent risk factors: High initial SAPS II for 30d-, multiple organ failure and high maximum SAPS II for 100d- and high maximum leukocyte count for long-term mortality. Surgical intervention during ICU was an independent predictor of a better 30d outcome. CONCLUSIONS: In contrast to general IE populations, IA and the type of infected impaired valve are not main predictors of survival in critically ill IE-patients. Biomarker of acute infection and markers for severity of illness (scores and organ failure) are independent risk factors for mortality. The surgical clearance of infected valve, device or abscesses is an independent predictor of 30d outcome.

Increased factor XIa levels in patients with a first acute myocardial infarction: the introduction of a new thrombin generation based factor XIa assay.

OBJECTIVE: One of the contributing mechanisms in acute myocardial infarction (AMI) is plasma hypercoagulability. Recently, it was suggested that factor XI activation might play a role in atherothrombosis. To quantify factor XIa plasma levels, we developed a new thrombin generation based assay and hypothesized that in AMI patients factor XIa levels are increased during the acute thrombotic event. METHODS: A prospective cohort study was performed including 56 patients with first AMI. Blood was collected upon admission and after 6 months. Reference blood samples were obtained from 30 apparently healthy control subjects. Plasma samples were diluted (1:5) in factor XI deficient plasma and factor XIa plasma levels were established using a reference curve (0-12.5 pM factor XIa) and an inhibitory anti-factor XIa antibody. The established FXIa concentrations were related to the 1-year outcome. RESULTS: Factor XIa plasma concentrations were significantly increased in AMI patients on admission compared to 6 months after the event (3.7 pM [2.7-5.5] vs. 2.8 [1.9-4.3], median ± IQR; P=0.001) and compared to healthy controls (3.7 pM [2.7-5.5] vs. 2.7 [1.6-4.2], median ± IQR; P=0.004). However, a high factor FXIa level at baseline was not significantly associated with a recurrent cardiovascular event (OR 1.26, 95%CI 0.33-4.7). CONCLUSIONS: This study presents the first application of a new thrombin generation based factor XIa assay, showing significantly increased factor XIa levels in AMI patients on admission compared to 6 months after the event and compared to healthy controls. The factor XIa concentration was not associated with the risk of recurrence.

Arrhythmogenic right ventricular cardiomyopathy: an update on pathophysiology, genetics, diagnosis, and risk stratification.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy accounting for life-threatening ventricular tachyarrhythmias and sudden death in young individuals and athletes. Over the past years, mutations in desmosomal genes have been identified as disease-causative. However, genetic heterogeneity and variable phenotypic expression alongside with diverse disease progression still render the evaluation of its prognostic implication difficult. ARVC was initially entered into the canon of cardiomyopathies of the World Health Organization in 1995, and international efforts have resulted in the 2010 modified diagnostic criteria for ARVC. Despite all additional insights into pathophysiology, clinical management, and modern risk stratification, under-/misdiagnosing of ARVC remains a problem and hampers reliable statements on the incidence, prevalence, and natural course of the disease.This review provides a comprehensive overview of the current literature on the pathogenesis, diagnosis, treatment, and prognosis of ARVC and sheds some light on potential new developments in these areas.

Thrombin generation in patients with a first acute myocardial infarction.

BACKGROUND: Despite improved treatment options, myocardial infarction is still an important cause of morbidity and mortality. One of the contributing mechanisms in the acute myocardial infarction (AMI) is plasma hypercoagulability. METHODS: We investigated hypercoagulability in 135 (first) patients with AMI using thrombin generation (TG) testing. TG testing was performed in plasmas, drawn upon admission and before medication administration, and subsequently after 4 days, 3 and 6 months. Further, we evaluated determinants of thrombin generation using multiple regression analysis of major coagulation proteins and inhibitors. Admission TG results were also related to 1-year outcome: cardiovascular death, recurrent myocardial infarction, a second coronary intervention [percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)] and ischemic stroke. RESULTS: At day 0, the TG parameters peak height, endogenous thrombin potential (ETP) and lag time were increased compared with a reference population. Peak height and lag time stayed persistently increased in patients. The lowest half of the ETP values was statistically not significantly associated with an occurrence of endpoints. The lowest half of the ETP values combined with the upper half of the D-dimer values were associated with endpoints; odds ratio 5.8 (1.1-30.7). Tissue factor pathway inhibitor (TFPI) seems to be an important determinant of TG in AMI and healthy persons. CONCLUSIONS: TG reflects acute hypercoagulability during AMI and partly also in the 6-month period after the acute event. TG shows a trend of an inverse association with risk of recurrent ischemic cardiovascular complications. Unraveling mechanisms in TG might improve our understanding of the pathophysiology of AMI and direct future improvements in medical care.

Potentiating role of Gas6 and Tyro3, Axl and Mer (TAM) receptors in human and murine platelet activation and thrombus stabilization.

BACKGROUND: Interaction of murine Gas6 with the platelet Gas6 receptors Tyro3, Axl and Mer (TAM) plays an important role in arterial thrombus formation. However, a role for Gas6 in human platelet activation has been questioned. OBJECTIVE: To determine the role of Gas6 in human and murine platelet activation and thrombus formation. METHODS AND RESULTS: Gas6 levels appeared to be 20-fold higher in human plasma than in platelets, suggesting a predominant role of plasma-derived Gas6. Human Gas6 synergizes with ADP-P2Y(12) by enhancing and prolonging the phosphorylation of Akt. Removal of Gas6 from plasma impaired ADP-induced platelet aggregation. Under flow conditions, absence of human Gas6 provoked gradual platelet disaggregation and integrin α(IIb) ß(3) inactivation. Recombinant human Gas6 reversed the effects of Gas6 removal. In mouse blood, deficiency in Gas6 or in one of the TAM receptors led to reduced thrombus formation and increased disaggregation, which was completely antagonized by external ADP. In contrast, collagen-induced platelet responses were unchanged by the absence of Gas6 in both human and mouse systems. CONCLUSIONS: The ADP-P2Y(12) and Gas6-TAM activation pathways synergize to achieve persistent α(IIb) ß(3) activation and platelet aggregation. We postulate a model of thrombus stabilization in which plasma Gas6, by signaling via the TAM receptors, extends and enhances the platelet-stabilizing effect of autocrine ADP, particularly when secretion becomes limited.

Diabetes mellitus impairs CD133+ progenitor cell function after myocardial infarction.

BACKGROUND: Circulating progenitor cells (PC) can positively influence the healing of ischaemic myocardium. Cardiovascular risk factors including diabetes mellitus (DM) may have a negative influence on both number and recruitment of PC. Recent evidence suggests that less differentiated CD133(+)PC contribute to myocardial healing and are promising candidates for therapy. Therefore, we investigated whether DM affects CD133(+)PC. METHODS: CD133(+)PC were analyzed in patients following acute myocardial infarction and successful reperfusion [acute myocardial infarction (AMI, n=45) with/without non-insulin-requiring type 2 DM (T2DM)]. Stable coronary artery disease patients (CAD, n = 45) served as stable controls. Number and phenotype of CD133(+)PC were assessed by flow cytometry. CD133(+)PC chemotaxis was assessed towards vascular endothelial growth factor, an angiogenic stimulus upregulated in AMI. The expression of anti-oxidant enzymes in CD133(+)PC was detected by reverse-transcriptase PCR. RESULTS: In non-DM patients, the number of CD133(+)PC increased on day 3 following AMI (P=0.0001). In contrast, no changes were observed in AMI patients with T2DM. Regarding the function of CD133(+)PC, an enhanced chemotactic response was observed following AMI in both non-DM (P=0.0001) and T2DM (P=0.007). However, the AMI-related functional activation was significantly weaker in diabetic patients (P=0.001). Moreover, the expression of catalase was lower in CD133(+)PC from T2DM. CONCLUSIONS: Our results show that T2DM not only limits the abundance of CD133(+)PC following AMI, but also limits their activation. This might be explained by a lower resistance of CD133(+)PC to oxidative stress. Our data provide a possible explanation for the delayed postischaemic vascular healing and myocardial recovery in DM.