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Aims: This study aimed to analyse changes in pre-hospital delay over time in women and men presenting with ST-elevation myocardial infarction (STEMI) in Switzerland., Methods and Results: AMIS Plus registry data of patients admitted for STEMI between 2002 and 2019 were analysed using multivariable quantile regression including the following covariates: interaction between sex and admission year, age, diabetes, pain at presentation, myocardial infarction (MI) history, heart failure history, hypertension, and renal disease. Among the 15,350 patients included (74.5% men), the median (interquartile range) delay between 2002 and 2019 was 150 (84; 345) min for men and 180 (100; 414) min for women. The unadjusted median pre-hospital delay significantly decreased over time for both sexes but the decreasing trend was stronger for women. Specifically, the unadjusted sex differences in delay decreased from 60 min in 2002 (P = 0.0042) to 40.5 min in 2019 (P = 0.165). The multivariable model revealed a significant interaction between sex and admission year (P = 0.038) indicating that the decrease in delay was stronger for women (-3.3 min per year) than for men (-1.6 min per year) even after adjustment. The adjusted difference between men and women decreased from 26.93 min in 2002 to -1.97 min for women in 2019., Conclusion: Over two decades, delay between symptom onset and hospital admission in STEMI decreased significantly for men and women. The decline was more pronounced in women, leading to the sex gap disappearing in the adjusted analysis for 2019., Competing Interests: Conflict of interest: None declared, (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Despite guideline recommendations, previous reports, coming mainly from outside Europe, showed low rates of prescriptions for dual antiplatelet therapy (DAPT) in patients with acute myocardial infarction (AMI) undergoing surgical revascularization. The present study assesses this issue in the era of potent P2Y12 inhibitors in Switzerland., Methods: All patients with a diagnosis of AMI included in the Acute Myocardial Infarction in Switzerland Plus Registry from January 2014 to December 2019 were screened; 9050 patients undergoing either percutaneous (8727, 96.5%) or surgical (323, 3.5%) revascularization were included in the analysis., Results: Surgically treated patients were significantly less likely to receive DAPT at discharge (56.3% vs 96.7%; P < 0.001). Even when discharged with a prescription for DAPT, those patients were significantly less likely to receive a regimen containing a new P2Y12 inhibitor (67/182 [36.8%] vs 6945/8440 [83.2%]; P < 0.001). At multivariate analysis, surgical revascularization was independently associated with a lower likelihood of receiving a prescription for DAPT at discharge (odds ratio 0.03, 95% confidence interval 0.02-0.06)., Conclusions: DAPT prescriptions for patients with AMI undergoing surgical revascularization are not in line with current guideline recommendations. Efforts are necessary to clarify the role of DAPT for secondary prevention in these patients and increase the confidence of treating physicians in guideline recommendations., Clinical Trial Registration: Acute Myocardial Infarction in Switzerland Plus Registry; registration number at ClinicalTrials.gov: NCT01305785., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aims: Among acute coronary syndromes (ACS), ST-segment elevation myocardial infarction (STEMI) has the most severe early clinical course. Recent randomized clinical trials have demonstrated that novel antithrombotic therapies improve in-hospital outcomes in STEMI patients. We aimed to describe the effectiveness and safety of P2Y12 receptor inhibitors in clinical practice in patients with STEMI based on data from contemporary European ACS registries., Methods and Results: Five registries from the PIRAEUS initiative (AAPCI/ADPAT, ALKK-PIC, AMIS Plus, Belgium STEMI, and EYESHOT) provided data for the assessment of P2Y12 receptor inhibitor-based dual antiplatelet therapy. Registries were heterogeneous in terms of setting, patient characteristics, and treatment selection. Matched pair analysis and propensity score matching were used to assess all-cause in-hospital death rates based on data from 25 250 patients (8577 patients on prasugrel, 5995 on ticagrelor, and 10 678 on clopidogrel). The odds ratio (OR) for the death of any cause when compared with clopidogrel was 0.72 [95% confidence interval (CI) 0.62-0.84, P < 0.001] in favour of the new P2Y12 receptor inhibitors (prasugrel and ticagrelor combined). In the comparison between prasugrel and ticagrelor, there were no relevant differences (OR 0.97, 95% CI 0.77-1.23; P = 0.81). Event rates of cardiovascular death and stroke were also substantially lower for the new P2Y12 receptor inhibitors. The differences between clopidogrel and prasugrel or ticagrelor on major bleeding were numerically in the same order as for death of any cause but were not statistically significant. No differences in ischaemic and bleeding outcomes were observed between prasugrel and ticagrelor., Conclusion: This analysis suggests that the prasugrel or ticagrelor compared with clopidogrel have favourable outcomes in clinical practice while not being inferior in terms of safety., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Limited data are available on the impact of multisite artery disease in patients with acute coronary syndromes. In particular, it is unknown whether the outcomes of those high-risk patients have improved over time. Therefore, we addressed the multisite artery disease patient population enrolled in the Swiss nationwide prospective acute coronary syndromes cohort study AMIS Plus over two decades., Methods: All patients enrolled from January 1999 to October 2016 were stratified according to the presence of isolated coronary artery disease or multisite artery disease, defined as coronary artery disease with known concomitant vascular disease (i.e. cerebrovascular disease and/or peripheral artery disease). Multisite artery disease 1 (MSAD1) and multisite artery disease 2 (MSAD2) defined patients with one and two additional vascular conditions, respectively. Primary outcome measures were in-hospital mortality and major adverse cardiovascular events (defined as re-infarction, stroke or death)., Results: Among a total of 44,157 patients, 39,613 (89.7%) had coronary artery disease only while 4544 (10.3%) had multisite artery disease (4097 (9.3%) had MSAD1 and 447 (1.0%) had MSAD2). Compared with patients with coronary artery disease only, multisite artery disease patients were older, had a longer delay from symptom onset to hospital admission, had more frequently atypical presentation, presented more frequently with non-ST-segment elevation acute coronary syndromes, were more frequently in Killip class III/IV, had higher Charlson comorbidity index, more frequently had three-vessel coronary artery disease and were treated less frequently with evidence-based treatments such as aspirin, P2Y 12 inhibitors, or beta-blockers. Similarly, multisite artery disease benefitted less frequently from coronary angiography as well as percutaneous coronary revascularisation. In-hospital mortality was 10.9% in multisite artery disease patients and 4.4% in coronary artery disease-only patients ( P <0.001). Corresponding major adverse cardiovascular events rates were 13.4% and 5.4% ( P <0.001). Cardiogenic shock, re-infarction and cerebrovascular events were significantly more frequent in multisite artery disease patients compared with coronary artery disease-only patients. In multivariable logistic regression analysis, multisite artery disease was identified as an independent predictor of in-hospital mortality (odds ratio 1.69, 95% confidence interval 1.47-1.94, P <0.001). Among multisite artery disease patients, mortality was the highest in MSAD2 individuals (15.4% vs. 10.4% among MSAD1 patients, P =0.001), the same was true for the major adverse cardiovascular events rates (19.1% in MSAD2 patients vs. 12.7% in MSAD1 patients, P <0.001). When stratified for the decade of enrollment, no improvement in mortality or major adverse cardiovascular events rates was observed in multisite artery disease patients., Conclusion: Patients presenting with multisite artery disease were less likely to receive evidence-based therapies than coronary artery disease-only patients and had increased in-hospital morbidity and mortality, with no improvement over time. The worse outcomes were observed among MSAD2 patients. These results should prompt awareness for multisite artery disease as a high-risk condition in the setting of multisite artery disease.

Background: Cardiac rehabilitation after an acute myocardial infarction has a class I recommendation in the present guidelines. However, data about the impact on mortality in Switzerland are not available. Therefore, we analysed one-year outcome of acute myocardial infarction patients according to cardiac rehabilitation referral at discharge., Design and Methods: Data were extracted from the Swiss AMIS Plus registry and included patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction, who were asked to give their informed consent to a telephone follow-up one year after discharge., Results: From 10,141 patients, 1956 refused to participate in follow-up and 302 were lost to follow-up. There were 4508 (57.2%) patients with cardiac rehabilitation referrals compared with 3375 (42.8%) without. Patients referred to cardiac rehabilitation were younger (62.4 years vs. 68.8 years), more often male (77% vs. 70%), presented more often with ST-elevation myocardial infarction (63.5% vs. 52.1%) and, apart from smoking (44.0% vs. 34.9%), they had fewer risk factors, such as dyslipidaemia (55.0% vs. 60.1%), hypertension (55.6% vs. 65.3%) and diabetes (16.7% vs. 21.5%). Patients referred to cardiac rehabilitation had a lower crude one-year all-cause mortality (1.7% vs. 5.8%; p < 0.001) and lower rates of re-infarction, rehospitalization for cardiovascular disease and intervention (all p < 0.005). In a multivariable logistic regression analysis, cardiac rehabilitation was an independent predictor for lower mortality rate (odds ratio 0.65; 95% confidence interval 0.48-0.89; p = 0.007)., Conclusions: Although the detailed data of cardiac rehabilitation programmes and patient participation were not available for this study, our data from 7883 acute myocardial infarction patients showed a better one-year outcome for patients with cardiac rehabilitation referrals than for those without.

Background: Although cancer treatment considerably affects cardiovascular health, little is known about how cancer patients are treated for an acute myocardial infarction. We aimed to investigate whether acute myocardial infarction patients with a history of cancer received the same guideline recommended treatment as those acute myocardial infarction patients without and whether they differ with respect to inhospital outcome., Methods: All patients with ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction, enrolled between 2002 and mid-2015 in the acute myocardial infarction in Switzerland (AMIS Plus) registry with comorbidity data based on the Charlson comorbidity index were analysed. Patients were classified as having cancer if one of the cancer diseases of the Charlson comorbidity index was indicated. Immediate treatment strategies and inhospital outcomes were compared between groups using propensity score matching., Results: Of 35,249 patients, 1981 (5.6%) had a history of cancer. After propensity score matching for age, gender, Killip class >2, ST-segment elevation myocardial infarction and renal disease (1981 patients per group), significant differences were no longer found for a history of acute myocardial infarction, hypertension, diabetes, heart failure and cerebrovascular disease between cancer and non-cancer patients. However, cancer patients underwent percutaneous coronary intervention less frequently (odds ratio (OR) 0.76; 95% confidence interval (CI) 0.67-0.88) and received P2Y12 blockers (OR 0.82; 95% CI 0.71-0.94) and statins (OR 0.87; 95% CI 0.76-0.99) less frequently. Inhospital mortality was significantly higher in cancer patients (10.7% vs. 7.6%, OR 1.45; 95% CI 1.17-1.81). However, the main cause of death was cardiac in both groups ( P=0.06)., Conclusion: Acute myocardial infarction patients with a history of cancer were less likely to receive guideline recommended treatment and had worse inhospital outcomes than non-cancer patients.

Aims: Among patients with acute coronary syndromes (ACS), those with diabetes mellitus (DM) are at particularly high risk of recurrent cardiovascular events and premature death. We aimed to provide a descriptive overview of unadjusted analyses of patient characteristics, ACS management, and outcomes up to 1 year after hospital admission for an ACS/index-ACS event, in patients with DM in contemporary registries in Europe., Methods and Results: A total of 10 registries provided data in a systematic manner on ACS patients with DM (total n =28 899), and without DM (total n= 97 505). In the DM population, the proportion of patients with ST-Segment Elevation Myocardial Infarction (STEMI) ranged from 22.1% to 64.6% (other patients had non-ST-Segment Elevation Myocardial Infarction (NSTEMI-ACS) or unstable angina). All-cause mortality in the registries ranged from 1.4% to 9.4% in-hospital; 2.8% to 7.9% at 30 days post-discharge; 5.1% to 10.7% at 180 days post-discharge; and 3.3% to 10.5% at 1 year post-discharge. Major bleeding events were reported in up to 3.8% of patients while in hospital (8 registries); up to 1.3% at 30 days (data from two registries only), and 2.0% at 1 year (one registry only). Registries differed substantially in terms of study setting, site, patient selection, definition and schedule of endpoints, and use of various P2Y12 inhibitors. In most, but not all, registries, event rates in DM patients were higher than in patients without DM. Pooled risk ratios comparing cohorts with DM vs. no DM were in-hospital significantly higher in DM for all-cause death (1.66; 95% CI 1.42-1.94), for cardiovascular death (2.33; 1.78 - 3.03), and for major bleeding (1.35; 1.21-1.52)., Conclusion: These registry data from real-life clinical practice confirm a high risk for recurrent events among DM patients with ACS, with great variation across the different registries., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Aims: Non-ST-elevation acute coronary syndrome (NSTE-ACS) is present in about 60-70% of patients admitted with acute coronary syndromes in clinical practice. This study provides a 'real-life' overview of NSTE-ACS patient characteristics, dual antiplatelet therapy clinical practice, and outcomes at both the time of discharge from hospital and up to 1-year post-discharge., Methods and Results: A total of 10 registries (documenting 84 054 NSTE-ACS patients) provided data in a systematic manner on patient characteristics and outcomes for NSTE-ACS in general, and 6 of these (with 52 173 NSTE-ACS patients) also provided more specific data according to P2Y12 receptor inhibitor used. Unadjusted analyses were performed at the study level, and no formal meta-analysis was performed due to large heterogeneity between studies in the settings, patient characteristics, and outcome definitions. All-cause death rates across registries ranged from 0.76 to 4.79% in-hospital, from 1.61 to 6.65% at 30 days, from 3.66 to 7.16% at 180 days, and from 3.14 to 9.73% at 1 year. Major bleeding events were reported in up to 2.77% of patients while in hospital (in seven registries), up to 1.08% at 30 days (data from one registry only), and 2.06% at 1 year (one registry)., Conclusions: There were substantial differences in the use of and patient selection for clopidogrel, prasugrel, and ticagrelor, which were associated with differences in short- and long-term ischaemic and bleeding events. In future registries, data collection should be performed in a more standardized way with respect to endpoints, definitions, and time points., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: Patients presenting very early after chest pain onset may provide a diagnostic challenge even when using a high-sensitivity cardiac troponin (hs-cTnT). We hypothesized that in these patients the incremental value of copeptin in the early diagnosis of acute myocardial infarction (AMI) may be substantial., Methods: We aimed to investigate the incremental value of copeptin in a pre-specified subgroup analysis of patients presenting with suspected AMI to the emergency department within 2 hours of symptom onset in a multicenter study. Copeptin was measured in a blinded fashion. Two independent cardiologists adjudicated the final diagnosis using all available clinical informations, including high-sensitivity cardiac troponin T (hs-cTnT)., Results: Overall, 2000 patients were enrolled, of whom 519 (26%) arrived within 2 hours of symptom onset. Of these, 102 patients (20%) had an AMI. The additional use of copeptin did not increase diagnostic accuracy as quantified by the area under the receiver-operating characteristic curve (AUC) of hs-cTnT (0.87 (95% confidence interval (CI): 0.83-0.90) for hs-cTnT alone to 0.86 (95% CI: 0.82-0.90) for the combination; p = NS). Copeptin (using 9 pmol/L as a cut-off) increased the negative predictive value (NPV) of hs-cTnT (using 14 ng/L as a cut-off) alone from 93% (95% CI: 90-95%) to 96% (95% CI: 93-98%). The NPV for the combination of hs-cTnT and copeptin was lower in patients arriving in the first 2 hours than in those arriving after 2 hours: 96% (95% CI: 93-98%) versus 99% (95% CI: 99-100%), respectively., Conclusions: The additional use of copeptin on top of hs-cTnT seems to lead to a small increase in NPV, but no increase in AUC. Routine use of copeptin in early presenters does not seem warranted., (© The European Society of Cardiology 2016.)

Aims: Battery exchange in pacemaker (PM) or implantable cardioverter defibrillator (ICD) devices may be occasionally problematic because of difficulties in lead disconnection procedures and risk of injuring the fragile leads. This pilot study compares ethanol and dimethyl sulfoxide (DMSO) as solvents to assist removal of leads from PM or ICD device headers in cases of stuck leads or difficulties in untightening device header screws., Methods and Results: Of the total number (527) of our patients requiring battery replacement due to end-of-life (EOL) warnings, conventional exchange was not possible in 34 (6.5%) due to embedding of the lead within blood-derived material. Of these, 30 (17 with PM, 13 with ICD) consented to the study and were randomly assigned to a primary attempt at lead disconnection by ethanol (n = 17) or by DMSO (n = 13). If the primary attempt failed, a secondary attempt at lead disconnection was undertaken using the alternate solvent. Ethanol was a superior solvent compared with DMSO, yielding successful disconnection at primary attempt in 88.2% (15/17) vs. 23.1% (3/13) of cases. In 8 patients in whom the primary DMSO-attempted disconnection failed, a secondary attempt with ethanol yielded success in 6 (75%) cases. Use of either ethanol or DMSO in lead disconnection was not associated with any adverse events or effects., Conclusion: Ethanol has utility as a simple and inexpensive modality for lead disconnection from ICD or PM headers., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: Among acute coronary syndromes (ACS), ST-segment elevation myocardial infarction (STEMI) has the most severe early clinical course. We aimed to describe the effectiveness and safety of P2Y12 receptor inhibitors in patients with STEMI based on the data from contemporary European ACS registries., Methods and Results: Twelve registries provided data in a systematic manner on outcomes in STEMI patients overall, and seven of these also provided data for P2Y12 receptor inhibitor-based dual antiplatelet therapy. The registries were heterogeneous in terms of site, patient, and treatment selection, as well as in definition of endpoints (e.g. bleeding events). All-cause death rates based on the data from 84 299 patients (9612 patients on prasugrel, 11 492 on ticagrelor, and 27 824 on clopidogrel) ranged between 0.49 and 6.68% in-hospital, between 3.07 and 7.95% at 30 days (reported in 6 registries), between 8.15 and 9.13% at 180 days, and between 2.41 and 9.58% at 1 year (5 registries). Major bleeding rates were 0.09-3.55% in-hospital (8 registries), 0.09-1.65% at 30 days, and 1.96% at 1 year (only 1 registry). Fatal/life-threatening bleeding was rare occurring between 0.08 and 0.13% in-hospital (4 registries) and 1.96% at 1 year (1 registry)., Conclusions: Real-world evidence from European contemporary registries shows that death, ischaemic events, and bleeding rates are lower than those reported in Phase III studies of P2Y12 inhibitors. Regarding individual P2Y12 inhibitors, patients on prasugrel, and, to a lesser degree, ticagrelor, had fewer ischaemic and bleeding events at all time points than clopidogrel-treated patients. These findings are partly related to the fact that the newer agents are used in younger and less ill patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Aims: To determine whether treatment and outcomes of older acute coronary syndrome (ACS) patients changed over time., Methods and Results: We analysed the use of guideline-recommended therapies and in-hospital outcomes of 13 662 ACS patients ≥70 years enrolled in the prospective Acute Myocardial Infarction in Switzerland (AMIS) cohort between 2001 and 2012 according to 4-year periods (2001-2004, 2005-2008, and 2009-2012). Between first and last 4-year period, percutaneous coronary intervention (PCI) use increased from 43.8 to 69.6% of older ACS patients ( ITALIC! P < 0.001). Use of guideline-recommended drugs as well increased. At the same time, in-hospital mortality of the overall population decreased from 11.6% in the first to 10.0% in the last 4-year period ( ITALIC! P = 0.020), and in-hospital major adverse cardiac and cerebrovascular events from 14.4 to 11.3% ( ITALIC! P < 0.001). Percutaneous coronary intervention was used in increasingly older and co-morbid patients over time (mean age of patients treated with PCI 76.2 years in 2001-2004 and 78.1 years in 2009-2012, ITALIC! P < 0.001; Charlson score ≥2 was found for 27.6% of patients treated with PCI in 2001-2004 and for 32.1% in 2009-2012, ITALIC! P = 0.003). Percutaneous coronary intervention use was associated with similar odds ratios (ORs) of in-hospital mortality over time (adjusted OR 0.29, 95% confidence interval, CI, 0.22-0.40, in 2001-2004; and, adjusted OR 0.26, 95% CI 0.20-0.35, in 2009-2012)., Conclusion: Use of guideline-recommended therapies for ACS increased and in-hospital outcomes improved over the observed 12-year period. Though PCI was used in increasingly older and co-morbid patients, PCI use was associated with similar ORs of in-hospital mortality over time. This study suggests that increasing use of guideline-recommended therapies was appropriate., Trial Registration: ClinicalTrials.gov Identifier: NCT01305785., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: The early diagnosis of acute myocardial infarction (AMI) very soon after symptom onset remains a major clinical challenge, even when using high-sensitivity cardiac troponin (hs-cTnT)., Methods and Results: We investigated the incremental value of heart-type fatty acid-binding protein (hFABP) in a pre-specified subgroup analysis of patients presenting with suspected AMI within 1 h of symptom onset to the emergency department (ED) in a multicentre study. HFABP was measured in a blinded fashion. Two independent cardiologists using all available clinical information, including hs-cTnT, adjudicated the final diagnosis. Overall, 1411 patients were enrolled, of whom 105 patients presented within 1 h of symptom onset. Of these, 34 patients (32.4%) had AMI. The diagnostic accuracy as quantified by the area under the receiver-operating characteristics curve (AUC) of hFABP was high (0.84 (95% CI 0.74-0.94)). However, the additional use of hFABP only marginally increased the diagnostic accuracy of hs-cTnT (AUC 0.88 (95% CI 0.81-0.94) for hs-cTnT alone to 0.90 (95% CI 0.83-0.98) for the combination; p=ns). After the exclusion of 18 AMI patients with ST-segment elevation, similar results were obtained. Among the 16 AMI patients without ST-segment elevation, six had normal hs-cTnT at presentation. Of these, hFABP was elevated in two (33.3%) patients., Conclusions: hFABP does not seem to significantly improve the early diagnostic accuracy of hs-cTnT in the important subgroup of patients with suspected AMI presenting to the ED very early after symptom onset., (© The European Society of Cardiology 2015.)

Objective: The purpose of this study was to investigate outcomes of patients treated with prasugrel or clopidogrel after percutaneous coronary intervention (PCI) in a nationwide acute coronary syndrome (ACS) registry., Background: Prasugrel was found to be superior to clopidogrel in a randomized trial of ACS patients undergoing PCI. However, little is known about its efficacy in everyday practice., Methods: All ACS patients enrolled in the Acute Myocardial Infarction in Switzerland (AMIS)-Plus registry undergoing PCI and being treated with a thienopyridine P2Y12 inhibitor between January 2010-December 2013 were included in this analysis. Patients were stratified according to treatment with prasugrel or clopidogrel and outcomes were compared using propensity score matching. The primary endpoint was a composite of death, recurrent infarction and stroke at hospital discharge., Results: Out of 7621 patients, 2891 received prasugrel (38%) and 4730 received clopidogrel (62%). Independent predictors of in-hospital mortality were age, Killip class >2, STEMI, Charlson comorbidity index >1, and resuscitation prior to admission. After propensity score matching (2301 patients per group), the primary endpoint was significantly lower in prasugrel-treated patients (3.0% vs 4.3%; p=0.022) while bleeding events were more frequent (4.1% vs 3.0%; p=0.048). In-hospital mortality was significantly reduced (1.8% vs 3.1%; p=0.004), but no significant differences were observed in rates of recurrent infarction (0.8% vs 0.7%; p=1.00) or stroke (0.5% vs 0.6%; p=0.85). In a predefined subset of matched patients with one-year follow-up (n=1226), mortality between discharge and one year was not significantly reduced in prasugrel-treated patients (1.3% vs 1.9%, p=0.38)., Conclusions: In everyday practice in Switzerland, prasugrel is predominantly used in younger patients with STEMI undergoing primary PCI. A propensity score-matched analysis suggests a mortality benefit from prasugrel compared with clopidogrel in these patients., (© The European Society of Cardiology 2015.)

Patient registries that document real-world clinical experience play an important role in cardiology as they complement the data from randomized controlled trials, provide valuable information on drug use and clinical outcomes, and evaluate to what extent guidelines are followed in practice. The Platelet Inhibition Registry in ACS EvalUation Study (PIRAEUS) project is an initiative of registry holders who are managing national or international registries observing patients with acute coronary syndromes (ACS). The aim of PIRAEUS is to systematically compare and combine available information/insights from various European ACS registries with a focus on P2Y12 inhibitors. The present publication introduces the 17 participating registries in a narrative and tabular form, and describes which ACS groups and which dual antiplatelet therapies were investigated. It sets the basis for upcoming publications that will focus on effectiveness and safety of the antiplatelets used., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: This study evaluated associations between plasma T-cadherin levels and severity of atherosclerotic disease., Methods and Results: Three hundred and ninety patients undergoing coronary angiography were divided into three groups based on clinical and angiographic presentation: a group (n=40) with normal coronary arteries, a group (n=250) with chronic coronary artery disease and a group (n=100) with acute coronary syndrome. Plasma T-cadherin levels were measured by double sandwich ELISA. Intravascular ultrasound data of the left-anterior descending artery were acquired in a subgroup of 284 patients. T-cadherin levels were lower in patients with acute coronary syndrome than in normal patients (p=0.007) and patients with chronic coronary artery disease (p=0.002). Levels were lower in males (p=0.002), in patients with hypertension (p=0.002) and inpatients with diabetes (p=0.008), and negatively correlated with systolic blood pressure (p=0.014), body mass index (p=0.001) and total number of risk factors (p=0.001). T-cadherin negatively associated with angiographic severity of disease (p=0.001) and with quantitative intravascular ultrasound measures of lesion severity (p<0.001 for plaque, necrotic core and dense calcium volumes). Significant associations between T-cadherin and intravascular ultrasound measurements persisted even if the regression model was adjusted for the presence of acute coronary syndrome. Multivariate analysis identified a strong (p=0.002) negative association of T-cadherin with acute coronary syndrome, and lower T-cadherin levels significantly (p=0.002) associated with a higher risk of acute coronary syndrome independently of age, gender and cardiovascular risk factors., Conclusions: A reduction in plasma T-cadherin levels is associated with increasing severity of coronary artery disease and a higher risk for acute coronary syndrome., (© The European Society of Cardiology 2014.)

Background: In contrast to ST-elevation myocardial infarction (STEMI), in non-STEMI (NSTEMI) patients the need for continuous rhythm monitoring in a coronary care unit, respective incidence and timing of serious arrhythmias are poorly defined., Methods: We used a derivation-validation design and data from two independent prospective cohorts of consecutive haemodynamically stable NSTEMI patients to evaluate the incidence and timing of serious arrhythmias after successful early percutaneous revascularization. Serious arrhythmia was prospectively defined as any arrhythmia that requires immediate medical attention including persistent ventricular tachycardia (>30 s), ventricular fibrillation, asystole, and high degree atrioventricular (AV)-block requiring pacemaker insertion during hospitalization., Results: In the derivation cohort, among 228 NSTEMI patients who underwent successful early percutaneous revascularization, one patient (0.4%, 95% confidence interval 0.02-2.8%) had a serious arrhythmia which occurred 21 h after revascularization. In the validation cohort, among 293 NSTEMI patients who underwent successful early percutaneous revascularization, no patient (0%, 95% confidence interval 0-1.6%) had a serious arrhythmia after revascularization., Conclusion: The incidence of serious arrhythmias in NSTEMI patients after successful early revascularization seems to be very low., (© The European Society of Cardiology 2014.)

Aims: Takotsubo cardiomyopathy (TTC) remains a potentially life-threatening disease, which is clinically indistinguishable from acute myocardial infarction (MI). Today, no established biomarkers are available for the early diagnosis of TTC and differentiation from MI. MicroRNAs (miRNAs/miRs) emerge as promising sensitive and specific biomarkers for cardiovascular disease. Thus, we sought to identify circulating miRNAs suitable for diagnosis of acute TTC and for distinguishing TTC from acute MI., Methods and Results: After miRNA profiling, eight miRNAs were selected for verification by real-time quantitative reverse transcription polymerase chain reaction in patients with TTC (n = 36), ST-segment elevation acute myocardial infarction (STEMI, n = 27), and healthy controls (n = 28). We quantitatively confirmed up-regulation of miR-16 and miR-26a in patients with TTC compared with healthy subjects (both, P < 0.001), and up-regulation of miR-16, miR-26a, and let-7f compared with STEMI patients (P < 0.0001, P < 0.05, and P < 0.05, respectively). Consistent with previous publications, cardiac specific miR-1 and miR-133a were up-regulated in STEMI patients compared with healthy controls (both, P < 0.0001). Moreover, miR-133a was substantially increased in patients with STEMI compared with TTC (P < 0.05). A unique signature comprising miR-1, miR-16, miR-26a, and miR-133a differentiated TTC from healthy subjects [area under the curve (AUC) 0.835, 95% CI 0.733-0.937, P < 0.0001] and from STEMI patients (AUC 0.881, 95% CI 0.793-0.968, P < 0.0001). This signature yielded a sensitivity of 74.19% and a specificity of 78.57% for TTC vs. healthy subjects, and a sensitivity of 96.77% and a specificity of 70.37% for TTC vs. STEMI patients. Additionally, we noticed a decrease of the endothelin-1 (ET-1)-regulating miRNA-125a-5p in parallel with a robust increase of ET-1 plasma levels in TTC compared with healthy subjects (P < 0.05)., Conclusion: The present study for the first time describes a signature of four circulating miRNAs as a robust biomarker to distinguish TTC from STEMI patients. The significant up-regulation of these stress- and depression-related miRNAs suggests a close connection of TTC with neuropsychiatric disorders. Moreover, decreased levels of miRNA125a-5p as well as increased plasma levels of its target ET-1 are in line with the microvascular spasm hypothesis of the TTC pathomechanism.

Background: Data on temporal trends in outcomes, gender differences, and adherence to evidence-based therapy (EBT) of diabetic patients with ST-segment elevation myocardial infarction (STEMI) are sparse., Methods: We performed a retrospective analysis of prospectively acquired data on 3565 diabetic (2412 males and 1153 females) STEMI patients enrolled in the Swiss AMIS Plus registry between 1997 and 2010 and compared in-hospital outcomes and adherence to EBT with the nondiabetic population (n=15,531)., Results: In-hospital mortality dramatically decreased in diabetic patients, from 19.9% in 1997 to 9.0% in 2010 (p trend<0.001) with an age-adjusted decrease of 6% per year of admission. Similar trends were observed for age-adjusted reinfarction (OR 0.86, p<0.001), cardiogenic shock (OR 0.88, p<0.001), as well as death, reinfarction, or stroke (OR 0.92, p<0.001). However, the mortality benefit over time was observed in diabetic males (p trend=0.006) but not females (p trend=0.082). In addition, mortality remained twice as high in diabetic patients compared with nondiabetic ones (12.1 vs. 6.1%, p<0.001) and diabetes was identified as independent predictor of mortality (OR 1.23, p=0.022). Within the diabetic cohort, females had higher mortality than males (16.1 vs. 10.2%, p<0.001) and female gender independently predicted in-hospital mortality (OR 1.45, p=0.015). Adherence to EBT significantly improved over time in diabetic patients (p trend<0.001) but remained inferior - especially in women - to the one of nondiabetic individuals., Conclusions: In-hospital mortality and morbidity of diabetic STEMI patients in Switzerland improved dramatically over time but, compared with nondiabetic counterparts, gaps in outcomes as well as EBT use persisted, especially in women.

Aims: Catheter-based renal nerve ablation (RNA) using radiofrequency energy is a novel treatment for drug-resistant essential hypertension. However, the local endothelial and vascular injury induced by RNA has not been characterized, although this importantly determines the long-term safety of the procedure. Optical coherence tomography (OCT) enables in vivo visualization of morphologic features with a high resolution of 10-15 µm. The objective of this study was to assess the morphological features of the endothelial and vascular injury induced by RNA using OCT., Methods and Results: In a prospective observational study, 32 renal arteries of patients with treatment-resistant hypertension underwent OCT before and after RNA. All pre- and post-procedural OCT pullbacks were evaluated regarding vascular changes such as vasospasm, oedema (notches), dissection, and thrombus formation. Thirty-two renal arteries were evaluated, in which automatic pullbacks were obtained before and after RNA. Vasospasm was observed more often after RNA then before the procedure (0 vs. 42%, P < 0.001). A significant decrease in mean renal artery diameter after RNA was documented both with the EnligHTN (4.69 ± 0.73 vs. 4.21 ± 0.87 mm; P < 0.001) and with the Simplicity catheter (5.04 ± 0.66 vs. 4.57 ± 0.88 mm; P < 0.001). Endothelial-intimal oedema was noted in 96% of cases after RNA. The presence of thrombus formations was significantly higher after the RNA then before ablation (67 vs. 18%, P < 0.001). There was one evidence of arterial dissection after RNA with the Simplicity catheter, while endothelial and intimal disruptions were noted in two patients with the EnligHTN catheter., Conclusion: Here we show that diffuse renal artery constriction and local tissue damage at the ablation site with oedema and thrombus formation occur after RNA and that OCT visualizes vascular lesions not apparent on angiography. This suggests that dual antiplatelet therapy may be required during RNA.

Background: Smoking is one of the most important risk factors for myocardial infarction. Smokers usually suffer their first myocardial infarction earlier in life compared to non-smokers. This age difference seems to be greater in women than in men. The aim of this study was to examine the age and sex differences in terms of smoking in patients with first myocardial infarction who were enrolled in the Swiss National Registry of myocardial infarction, AMIS Plus., Methods: Data of 15,711 patients admitted to an AMIS Plus hospital between 1999 and 2008 with a first myocardial infarction were analysed. Several multivariate regression, interaction and sensitivity analyses were conducted., Results: The mean age at first myocardial infarction was 68.5 ± 12.2 years for non-smokers and 56.6 ± 11.7 years for smokers (P < 0.001). After stratification by sex the difference between non-smokers and smokers was 10.2 years in men and 13.1 years in women. Even after adjustment for risk factors (overweight, hypertension, dyslipidaemia, diabetes), comorbidities (peripheral vascular disease, cerebrovascular disease, chronic lung disease), regular cardiovascular medication intake before admission, Killip classification and ECG on admission, male smokers were 8.7 years younger than male non-smokers at first myocardial infarction. In women, the age difference between smokers and non-smokers was 10.8 years, giving a sex-specific difference of 2.1 years (P < 0.001)., Conclusions: In the AMIS Plus cohort, smoking was associated with younger age at first myocardial infarction and this was much more pronounced in women. Public health campaigns should take into account the impact of smoking on premature first myocardial infarction, especially in women.

Background: Few data are available concerning the impact of gender on temporal trends in patients with acute ST-segment elevation myocardial infarction (STEMI)., Methods: All STEMI patients consecutively enrolled in the AMIS (Acute Myocardial Infarction in Switzerland) Plus project from 1997-2011 were included. Temporal trends in presentation, treatment and outcomes were analyzed using multiple logistic regressions with generalized estimations., Results: Of 21,620 STEMI patients, 5786 were women and 15,834 men from 78 Swiss hospitals. Women were 8.6 years older, presented 48 minutes later with less pain, but more dyspnea, and more frequently had atrial fibrillation (5.5 vs. 3.9%, p<0.001), heart failure (Killip class >2) (9.7 vs. 7.3%, p<0.001), and moderate or severe comorbidities (24.8 vs. 18.2%, p<0.001). Women were less likely to undergo primary reperfusion treatment after adjustment for baseline characteristics and admission year (OR 0.80, 95% CI 0.71-0.90, p<0.001) or receive early and discharge drugs, such as thienopyridines, angiotensin-converting-enzyme inhibitors, angiotensin II receptor antagonists, and statins. In 1997, thrombolysis was performed in 51% of male and 39% of female patients; its use rapidly decreased during the 1990s and has now become negligible. Primary percutaneous coronary intervention increased from under 10% in both genders in 1997 to over 70% in females and over 80% in males since 2006. Patients admitted in cardiogenic shock increased by 8% per year in both genders. The incidence of both reinfarction and cardiogenic shock developing during hospitalization decreased significantly over 15 years while in-hospital mortality decreased from 10 to 5% in men and from 18 to 7% in women. This corresponds to a relative reduction of 5% per year for males (OR 0.95, 95% CI 0.92-0.99, p=0.006) and 6% per year for female STEMI patients (OR 0.94, 95% CI 0.91-0.97, p<0.001). Despite higher crude in-hospital mortality, female gender per se was not an independent predictor of in-hospital mortality (OR 1.07, 95% CI 0.84-1.35, p=0.59)., Conclusion: Substantial changes have occurred in presentation, treatment, and outcome of men and women with STEMI in Switzerland over the past 15 years. Although parallel trends were seen in both groups, ongoing disparities in certain treatments remain. However, these did not translate into worse risk-adjusted in-hospital mortality, suggesting that the gender gap in STEMI care may be closing.

iNKT cells are a unique T cell subset, which is CD1d-restricted and specific for glycolipid antigens. In advanced atherosclerotic plaques, focal collections of inflammatory cells correlate with areas of intraplaque neovascularization. We reported recently that iNKT cells might facilitate intraplaque neovascularization by enhancing EC migration and sprouting in an IL-8-dependent manner. This study investigated the participating effector mechanisms. In ECs, CM, derived from antigen-stimulated human iNKT cells (CM+), induced up-regulation of IL-8R CXCR2 and the phosphorylation of EGFR and of multiple intracellular signaling effectors, including FAK, Src, Erk, Jnk, p38-MAPK, and STAT1 and -3. We found that a cascade of events, which were IL-8-dependent and involved EGFR activation, was responsible for signaling through FAK and Src kinases and necessary for acquisition of angiogenic morphology, migration in a two-dimensional wound assay, and sprout outgrowth in a three-dimensional model of angiogenesis in vitro. The data support that IL-8-dependent activation of angiogenic behavior in ECs, in response to activated iNKT, involves CXCR2, transactivation of EGFR, and subsequent FAK/Src signaling. We found too that activated iNKT increased VEGFR2 expression in ECs. Functional studies confirmed that EGF is the motogenic-enhancing factor in CM+ and is necessary, together with an exogenous source of VEGF, for iNKT-promoted sprout formation. EGFR inhibition may represent a novel therapeutic modality aimed at plaque stabilization through control of neovascularization within developing atherosclerotic plaques.

Aims: The presence of endothelial cell (EC)-derived surface molecules in the circulation is among hallmarks of endothelial activation and damage in vivo. Previous investigations suggest that upregulation of T-cadherin (T-cad) on the surface of ECs may be a characteristic marker of EC activation and stress. We investigated whether T-cad might also be shed from ECs and in amounts reflecting the extent of activation or damage., Methods and Results: Immunoblotting showed the presence of T-cad protein in the culture medium from normal proliferating ECs and higher levels in the medium from stressed/apoptotic ECs. Release of T-cad into the circulation occurs in vivo and in association with endothelial dysfunction. Sandwich ELISA revealed negligible T-cad protein in the plasma of healthy volunteers (0.90 ± 0.90 ng/mL, n = 30), and increased levels in the plasma from patients with non-significant atherosclerosis (9.23 ± 2.61 ng/mL, n = 63) and patients with chronic coronary artery disease (6.93 ± 1.31 ng/mL, n = 162). In both patient groups there was a significant (P = 0.043) dependency of T-cad and degree of endothelial dysfunction as measured by reactive hyperaemia peripheral tonometry. Flow cytometry analysis showed that the major fraction of T-cad was released into the EC culture medium and the plasma as a surface component of EC-derived annexin V- and CD144/CD31-positive microparticles (MPs). Gain-of-function and loss-of-function studies demonstrate that MP-bound T-cad induced Akt phosphorylation and activated angiogenic behaviour in target ECs via homophilic-based interactions., Conclusion: Our findings reveal a novel mechanism of T-cad-dependent signalling in the vascular endothelium. We identify T-cad as an endothelial MP antigen in vivo and demonstrate that its level in plasma is increased in early atherosclerosis and correlates with endothelial dysfunction.

Background: Cadherins play important roles in controlling keratinocyte growth, differentiation and survival. Atypical glycosylphosphatidylinositol-anchored T-cadherin (T-cad) is highly expressed in the basal keratinocyte layer of skin. The role of T-cad in keratinocyte biology and pathology is unclear., Objectives: To define the role of T-cad in the pathogenesis of cutaneous squamous cell carcinoma (SCC) through gain-of-function and loss-of-function studies in vitro and through examination of T-cad expression patterns in human cutaneous SCC specimens in relation to histological classification of degree of tumour differentiation., Methods: In vitro studies employed lentiviral-mediated overexpression/silencing of T-cad in normal human keratinocyte (HaCaT) and SCC (A431) cell lines, monolayer and multicellular spheroid culture models, cell morphology analyses and assays of random motility and invasion. Immunohistochemistry was performed on skin specimens from patients with actinic keratosis, Bowen disease or SCC., Results: In vitro, silencing of T-cad induced a morphologically elongated and disorganized cell phenotype, increased random motility and markedly enhanced invasive potential. Overexpression of T-cad induced a morphologically spread and compact cell phenotype and blunted invasive potential. In vivo, regional loss of T-cad expression was more frequent and prominent in SCC classified as moderately-to-poorly differentiated than in SCC classified as well differentiated. However, in both categories aberrant and/or absence of T-cad expression was associated with histological features of a potentially more malignant and invasive phenotype of cutaneous SCC., Conclusions: T-cad is a controlling determinant of SCC phenotype and invasive behaviour and its loss is associated with the process of malignant transformation from noninvasive to invasive SCC.

Background: Current knowledge about risk factors promoting hypertensive crisis originates from retrospective data. Therefore, potential risk factors of hypertensive crisis were assessed in a prospective longitudinal study., Methods: Eighty-nine patients of the medical outpatient unit at the University Hospital of Bern (Bern, Switzerland) with previously diagnosed hypertension participated in this study. At baseline, 33 potential risk factors were assessed. All patients were followed-up for the outcome of hypertensive crisis. Cox regression models were used to detect relationships between risk factors and hypertensive crisis (defined as acute rise of systolic blood pressure (BP) > or =200 mm Hg and/or diastolic BP > or =120 mm Hg)., Results: The mean duration of follow-up was 1.6 +/- 0.3 years (range 1.0-2.4 years). Four patients (4.5%) were lost to follow-up. Thirteen patients (15.3%) experienced hypertensive crisis during follow-up. Several potential risk factors were significantly associated with hypertensive crisis: female sex, higher grades of obesity, the presence of a hypertensive or coronary heart disease, the presence of a somatoform disorder, a higher number of antihypertensive drugs, and nonadherence to medication. As measured by the hazard ratio, nonadherence was the most important factor associated with hypertensive crisis (hazard ratio 5.88, 95% confidence interval 1.59-21.77, P < 0.01)., Conclusions: This study identified several potential risk factors of hypertensive crisis. Results of this study are consistent with the hypothesis that improvement of medical adherence in antihypertensive therapy would help to prevent hypertensive crises. However, larger studies are needed to assess potential confounding, other risk factors and the possibility of interaction between predictors.

Aims: Patient access to reperfusion therapy and the use of primary percutaneous coronary intervention (p-PCI) or thrombolysis (TL) varies considerably between European countries. The aim of this study was to obtain a realistic contemporary picture of how patients with ST elevation myocardial infarction (STEMI) are treated in different European countries., Methods and Results: The chairpersons of the national working groups/societies of interventional cardiology in European countries and selected experts known to be involved in the national registries joined the writing group upon invitation. Data were collected about the country and any existing national STEMI or PCI registries, about STEMI epidemiology, and treatment in each given country and about PCI and p-PCI centres and procedures in each country. Results from the national and/or regional registries in 30 countries were included in this analysis. The annual incidence of hospital admission for any acute myocardial infarction (AMI) varied between 90-312/100 thousand/year, the incidence of STEMI alone ranging from 44 to 142. Primary PCI was the dominant reperfusion strategy in 16 countries and TL in 8 countries. The use of a p-PCI strategy varied between 5 and 92% (of all STEMI patients) and the use of TL between 0 and 55%. Any reperfusion treatment (p-PCI or TL) was used in 37-93% of STEMI patients. Significantly less reperfusion therapy was used in those countries where TL was the dominant strategy. The number of p-PCI procedures per million per year varied among countries between 20 and 970. The mean population served by a single p-PCI centre varied between 0.3 and 7.4 million inhabitants. In those countries offering p-PCI services to the majority of their STEMI patients, this population varied between 0.3 and 1.1 million per centre. In-hospital mortality of all consecutive STEMI patients varied between 4.2 and 13.5%, for patients treated by TL between 3.5 and 14% and for patients treated by p-PCI between 2.7 and 8%. The time reported from symptom onset to the first medical contact (FMC) varied between 60 and 210 min, FMC-needle time for TL between 30 and 110 min, and FMC-balloon time for p-PCI between 60 and 177 min., Conclusion: Most North, West, and Central European countries used p-PCI for the majority of their STEMI patients. The lack of organized p-PCI networks was associated with fewer patients overall receiving some form of reperfusion therapy.

Aims: Pharmacological conditioning of the phrenic nerve can positively influence systolic performance, and diaphragm activation improves ventilatory function. Here we investigate whether pacing-induced diaphragmatic stimulation (PIDS) may improve left ventricular (LV) systolic function., Methods and Results: We studied a total of 35 patients (4 females, mean age 67 +/- 9 years, ejection fraction 61 +/- 14%) within 7 days following open heart surgery. The haemodynamic impact of different PIDS and ventricular pacing configurations and coupling intervals was tested in 132 episodes. Success of PIDS was assessed using fluoroscopy and palpation. Left ventricular systolic performance was recorded using the electromechanical activation time (EMAT) obtained through acoustic cardiography. Eighteen subjects were tested in the catheter laboratory and 17 in the intensive care unit. For both groups, EMAT significantly improved when the diaphragm was stimulated 20 ms after the onset of ventricular pacing. In all instances, PIDS could be induced with or without causing patient symptoms, and LV systolic performance improvement was comparable in symptomatic and asymptomatic modes. No desensitization of the diaphragm was observed following PIDS delivery 4-6 and 24 h following open heart surgery., Conclusion: Pacing-induced diaphragmatic stimulation, if synchronized to the onset of ventricular contraction with a fixed, non-zero coupling delay, can improve LV systolic function reproducibly for at least 1 h without causing patient symptoms. The absence of diaphragm desensitization further underscores the potential of PIDS as a practical therapeutic approach in device-based heart failure management.

Objective: Cardiothoracic surgery using the heart-lung machine (HLM) provokes a pronounced endocrine-metabolic response leading to circadian rhythm disturbances that affect postoperative morbidity. Focus has been laid on changes in melatonin metabolism. The effects of an extra-corporal artificial circulation have not been adequately addressed., Methods: Seventeen patients scheduled for open heart surgery using the HLM were compared with 15 patients undergoing major surgery without cardiopulmonary bypass (non-HLM). Late afternoon and night urinary 6-sulfatoxymelatonin were measured at baseline, immediately after the operation and on return to the normal ward. Mood disturbances were assessed at baseline and final sampling times using a standardized questionnaire (arbitrary units)., Results: Vital signs were comparable between groups. The difference (delta) between day and night melatonin levels was similar at baseline (HLM group 1.1 ng/ml, non-HLM group 1.4 ng/ml, p=0.25). Immediately following surgery melatonin day-night deltas were unchanged to baseline (HLM 1.0 ng/ml, p=0.67; non-HLM 0.8 ng/ml, p=0.46) but at final sampling normal circadian melatonin profile was abolished (-0.3 ng/ml, p=0.001 and 0.0 ng/ml, p=0.07). However, this effect was not different between the two studied groups (p=0.17). No mood disorders were detectable at baseline (HLM 8.0 vs non-HLM 7.0, p=0.97) and no changes occurred after surgery (7.0 vs 6.5, p=0.33). Overall, patients with a worsening psychological score had pronounced postoperative washout of afternoon-night melatonin delta (p=0.04)., Conclusions: We found no relevant influence of the HLM on perioperative circadian melatonin profiles. Additionally, no alterations in mood assessment before and after surgery were observed. However, worsening of psychological score was associated with a pronounced disruption of the normal circadian melatonin profile.

In patients with left ventricular output failure, the Impella left ventricular assist device increases total cardiac output despite a drop in output provided by the left ventricle itself. We present a patient with cardiogenic shock after myocardial infarction in whom an Impella recover 2.5 was implanted. Correct placement was ensured by fluoroscopy, pressure and current signals displayed on the console of the system, and transthoracic echocardiography. On follow-up, the Impella device was dislocated with the shaft of the device lying on the anterior mitral leaflet causing a functional mitral stenosis evident by an increased transmitral diastolic flow gradient. After removing the device, the patients' haemodynamics improved within minutes. Other than a mild regurgitation, mitral valve was without pathological findings. Although infrequent, this case shows a possible complication of the Impella ventricular assist device and highlights the importance of periodical echocardiographic surveillance, especially in patients who show a poor response to therapy.

Aims: It has been shown that optimizing atrioventricular (AV) and interventricular (VV) delay improves cardiac performance in patients with biventricular pacemakers. However, there is no standard method for optimization available yet. The aim of this study was to compare echocardiographic parameters-displacement imaging, A wave duration, and aortic velocity time integral (VTI)-and acoustic cardiography derived electromechanical activation time (EMAT) using different approaches of AV and VV delay optimization. We tested whether the initial optimization of the AV interval followed by VV optimization at that optimal AV interval or initial optimization of the VV interval followed by AV optimization at the determined optimal VV interval was accurate and consistent, and how this compared to testing every conceivable combination of AV and VV intervals available., Methods and Results: A group of 20 patients with biventricular pacemakers was included. Displacement imaging, A wave duration, and aortic VTI were determined at different combinations of AV (100, 150, 200, 250 ms) and VV (RV40, 0, LV40 ms) intervals. If AV duration was determined first, displacement imaging identified the best setting in 8/20, aortic VTI in 10/20, A duration in 13/20, and EMAT in 18/20 patients. With VV duration determined first, the best setting was more difficult to identify regardless of the method used. There was a poor agreement in optimal AV and VV delays of the different methods, and there was no single patient in whom all four methods yielded the same delay combination., Conclusion: It is advisable to measure a full grid of AV and VV delays to identify optimal settings rather than optimizing one of the two delays first. Different techniques for delay optimization resulted in different optimal delay combinations.

Aims: Electrocardiographic (ECG) changes in patients with ascites are not well studied. The aim of this study was to evaluate ECG changes in patients with ascites., Methods and Results: Prospective analysis of patients with ascites who were referred for paracentesis. Three ECGs were recorded before paracentesis. ECG 1 was a standard 12-lead ECG. For ECG 2 the precordial leads were placed 1 intercostal space (ICS) and for ECG 3, 2 ICS cranially. The sums (Sigma) of the QRS in ECG1 were compared with ECG 2 and 3. In six patients the same ECG protocol was performed after removal of ascites. Ten hospitalized patients without ascites served as controls. Twenty patients with ascites were analysed. Limbs leads low voltage was present in 11 patients and precordial low voltage in four patients. Cranial placement of the precordial electrodes increased SigmaQRS in all patients with ascites. The most prominent voltage changes appeared in the leads V4-V6 (+62%). Paracentesis of ascites normalized precordial leads low-voltage, while limbs leads low voltage remained. Cranial placement of the precordial electrodes in patients without ascites decreases SigmaV1-V6., Conclusion: We describe a phenomenon of precordial voltage changes in patients with ascites, not reported in the literature yet. By placing the precordial electrodes 1 and 2 ICS cranially the voltage changes can be 'corrected' and this should be done in all patients prior to further diagnostic workup. Removal of the ascites normalizes the precordial leads low voltage.

Aims: To determine the effect of anti-ischaemic drug therapy on long-term outcomes of asymptomatic patients without coronary artery disease (CAD) history but silent exercise ST-depression., Methods and Results: In a randomized multicentre trial, 263 of 522 asymptomatic subjects without CAD but at least one CAD risk factor in whom silent ischaemia by exercise ECG was confirmed by stress imaging were asked to participate. The 54 (21%) consenting patients were randomized to anti-anginal drug therapy in addition to risk factor control (MED, n = 26) or risk factor control-only (RFC, n = 28). They were followed yearly for 11.2 +/- 2.2 years. During 483 patient-years, cardiac death, non-fatal myocardial infarction, or acute coronary syndrome requiring hospitalization or revascularization occurred in 3 (12%) of MED vs. 17 (61%) of RFC patients (P < 0.001). In addition, MED patients had consistently lower rates of exercise-induced ischaemia during follow-up, and left ventricular ejection fraction remained unchanged (-0.7%, P = 0.597) in contrast to RFC patients in whom it decreased over time (-6.0%, P = 0.006)., Conclusion: Anti-ischaemic drug therapy and aspirin seem to reduce cardiac events in subjects with asymptomatic ischaemia type I. In such patients, exercise-induced ST-segment depression should be verified by stress imaging; if silent ischaemia is documented, anti-ischaemic drug therapy and aspirin should be considered.

Aim: To assess treatment effects of optimised medical therapy and PCI or CABG surgery on one-year outcome in patients 75 years old with chronic angina., Methods and Results: On-treatment analysis of the TIME data: all re-vascularised patients (REVASC n=174: 112 randomised to revascularisation and 62 to drugs with late revascularisation) were compared to all patients on continued drug therapy (MED n=127: 86 randomised to drugs and 41 to revascularisation only). Baseline characteristics of both groups were similar (age 80 +/- 4 years). Risk of death at one year (adjusted hazard ratio (HR)=1.31; 95%-CI: 0.58-2.99; P=0.52) and of death/infarction (adjusted hazard RATIO=1.77; 95%-CI 0.91-3.41; P=0.09) were comparable between REVASC and MED patients. Furthermore, the risk of death within 30 days was even slightly lower among REVASC patients (unadjusted hazard RATIO=0.73; 95%-CI: 0.21-2.53; P=0.98). Overall, REVASC patients had greater improvements in symptoms and well-being than MED patients (P<0.01). Surgical patients had similar mortality rates as angioplasty patients, but they also had greater symptomatic improvements (P<0.01)., Conclusion: Treated medically, elderly patients with chronic angina have a similarly high 30-day and one-year mortality as patients of the same age being re-vascularised; however, they can expect lower improvements in symptoms and well being.

Angiotensin II (AII) has been implicated as an important factor in the pathophysiology of heart diseases. Following the recent identification of two subtypes of the AII receptor in cardiac tissue of animals, we investigated the possible occurrence of these, or similar, subtypes in human atrial tissue. In right-atrial tissue from patients undergoing heart surgery, we determined the AII-receptor profile in receptor binding studies, using [125I]-angiotensin as radioligand and subtypes to identify and quantify AII-receptor subpopulations. In 35 patients (23 requiring coronary bypasses, 10 valvular surgery and two combined coronary and valvular surgery), the left-ventricular ejection fraction was determined in the preoperative phase, and right- and left-atrial pressure during surgery. In membranes of human right atria, AII receptors are present in high density (median: Bmax = 294 fmol.mg-1 protein, range: 111-2073) and two different subtypes can be distinguished. Type-1 receptors (AT1) accounted for 33 +/- 10% of the population whereas type-2 receptors (AT2) made up 67 +/- 10% of the population. There was no correlation between any of the measured cardiac functions and total AII-receptor density or receptor affinity. However, the percentage of AT1 receptors was higher in the atria of patients with normal right-atrial pressure; left-ventricular ejection fraction was positively and right-atrial pressure inversely correlated with the percentage of AT1 receptors (r = 0.740 and -0.901, respectively; P < 0.001, for both). Moreover, the percentage of AT2 receptors was directly correlated with the levels of left-atrial pressure (r = 0.853; P < 0.001). It is concluded that the ratio of AT1 to AT2 receptors correlates well with right-atrial pressure and left-ventricular function. This is a first indication of a possible involvement of AII-receptor subtypes in the pathophysiology of cardiac dysfunctions.

The relationship between the Ca2+ transport of platelet endoplasmic reticulum and hypertension was analyzed in 17 untreated patients exhibiting various degrees of hypertension. Each patient underwent a 24-h recording of ambulatory blood pressure. Platelets from patients were permeabilized with saponin and the rate of ATP-driven thapsigargin-sensitive Ca2+ uptake determined using the fluorescent Ca2+ indicator fluo-3. No relationship between blood pressure (systolic, diastolic, day, night) and the rate of Ca2+ uptake into the sacroplasmic reticulum of platelets was found. A weak but insignificant correlation between Ca2+ uptake and the heart rate was noted. Therefore, the increase in cytosolic Ca2+ of platelets in hypertension may not be due to changes of the activity of Ca2+ uptake into the sacroplasmic reticulum.

All the components of the renin-angiotensin system have been identified in the heart including the angiotensin II receptor subtypes AT1 and AT2. In the normal human heart, there is a decreasing receptor density from the right atrium to the left ventricle. In right atrial membranes prepared from pathological hearts, the percentage of AT1 receptor decreases with the severity of cardiac dysfunction whereas that of AT2 receptor increases. Treatment of hypertrophic rats with AT1 receptor antagonists inhibits cardiac hypertrophy and reverses the increase receptor density, indicating involvement of this Ang II receptor subtype. The role of the AT2 receptor is still largely unknown but it may be involved in cell growth and proliferation. The cloning of both AT1 and AT2 receptors as well as the availability of potent and selective antagonists will help us to understand better the functional role of Angiotensin II in cardiovascular disorders.

Lymphocyte subpopulations were measured before and after physical and psychological stress in 15 healthy subjects and correlated with plasma catecholamine and cortisol levels. During psychological stress monocytes (P less than 0.05), NK (P less than 0.01), B cells (P less than 0.05) and heart rate (P less than 0.001) increased, while catecholamines remained unchanged. With physical stress granulocytes, monocytes and all lymphocyte subsets increased significantly, although B cells rose more than T cells and T (suppressor) cells more than T (helper) cells. Thus the ratio of T/B cells and of Th/Ts cells decreased (P less than 0.001 and P less than 0.01). Adrenaline and noradrenaline concentrations increased (P less than 0.001), while cortisol remained unchanged. There was a negative relationship between adrenaline and the Th/Ts cell ratio before and after stress (P less than 0.05). Lymphocyte subpopulations from a different group of 4 healthy subjects were analysed before and after isoproterenol infusion. There was a small increase in Ts and B cells only (P less than 0.1) and a decrease of the T/B cell ratio (P less than 0.05). The predominant enrichment of circulating B, Ts and NK cells during short lasting adrenergic activation, as well as the relationship of the T cell changes to plasma adrenaline, suggest an immunoregulatory effect of the sympathetic nervous system in stress.

Increased arteriolar tone is the pathophysiological hallmark of essential hypertension and is determined by the intracellular free calcium concentration in the vascular smooth muscle cell. Calcium influx is an important determinant of vasoconstriction and excess calcium influx-dependent vasoconstriction has been shown by plethysmographical studies in patients with essential hypertension. Calcium antagonists acutely lower BP by reducing calcium influx, calcium concentration and peripheral resistance. The degree of the attendant sympathetic nerve reflex activation and counter-regulatory mechanisms determines the antihypertensive response of the individual. Chronic monotherapy with a calcium antagonist results in an antihypertensive response, which is directly related to the patient's age and pretreatment BP and indirectly related to plasma renin levels. The resulting reduction in after-load neither leads to reduced cerebral blood flow in hypertensive patients, nor aggravates congestive heart failure. Calcium antagonists are a useful alternative to diuretics, primarily in older patients with low renin levels, either alone or combined with any other antihypertensive drug, and provide effective and safe control of blood pressure.

In vascular muscle cells, two distinct types of functionally important calcium (Ca2+) channels, called transient (T) and sustained (L), are differentiated by dihydropyridine calcium antagonists (CaA). We studied the ratio of T/L Ca2+ channels in isolated, spontaneously contracting azygous venous cells of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) by quantitating Ca2+ currents and intracellular Ca2+ release. While total transmembranous Ca2+ current was not different between the two strains, the proportion of Ca2+ currents carried by L-type channels was enhanced in vascular muscle cells from SHR. We have recently compared subcellular distribution of intracellular free Ca2+ concentration in the same cells, at rest and during stimulation, by quantitation with a digital photon-counting camera. Fura-2 fluorescence intensity showed that Ca2+ release was principally from sarcoplasmic reticulum and that cells from SHR had higher levels of Ca2+ upon calcium channel stimulation, especially at the cell periphery. These findings suggest fundamental differences in SHR and WKY vascular muscle cells implicating the importance of changes in calcium channels, modulation of Ca2+ release, and Ca2+ uptake in SHR hypertension.

The effects of 4 h haemodialysis (15 patients) or 4 h haemofiltration (five patients) on plasma concentrations of atrial natriuretic peptide (ANP) were compared by means of a sensitive radioreceptor binding assay, and related to accompanying changes in body weight, blood pressure and plasma renin activity. Before dialysis, plasma ANP concentrations were considerably elevated: haemodialysis group 10-484 pmol/l (mean 156 pmol/l); haemofiltration group 72-320 pmol/l (mean 170 pmol/l). Although plasma concentrations of ANP fell markedly with treatment in both groups: post-haemodialysis 2-187 pmol/l (mean 67 pmol/l); post-haemofiltration 47-135 pmol/l (mean 79 pmol/l), after treatment it remained above the normal range in 14 of the 20 patients. Pretreatment plasma ANP was related to systolic blood pressure (r = 0.459; P less than 0.05) but bore no relationship to mean or diastolic blood pressure, or plasma renin activity. The fall in plasma ANP concentration during treatment correlated with the postural blood pressure drop after dialysis (r = 0.505; P less than 0.05), but was unrelated to changes in weight or plasma renin activity with haemodialysis or haemofiltration. Plasma ANP concentrations rose rapidly again in the 60 min after dialysis treatment, without change in body weight. These results show that high levels of biologically active ANP circulate in end-stage renal disease. The fact that these are not reduced to normal by haemodialysis or haemofiltration, despite restoration to normovolaemic or hypovolaemic state, suggests that the increased levels of ANP in end-stage renal failure are due to both hypervolaemia and other factors, which may include occult cardiac dysfunction and loss of renal clearance.