Publications by authors named "Roland Klingenberg"

75 Publications

Prognostic value of total testosterone levels in patients with acute coronary syndromes.

Eur J Prev Cardiol 2021 Apr;28(2):235-242

Cardiology Division, Geneva University Hospitals, Switzerland.

Background: Endogenous testosterone levels decrease in men with aging. Controversies persist regarding the screening and treatment of low testosterone levels in patients with acute coronary syndromes (ACS).

Methods And Results: Total serum testosterone levels were measured in 1054 men hospitalized for ACS that were part of a Swiss prospective cohort. Total testosterone levels were classified first in tertiles and using the cut-off of 300 ng/dL. Primary endpoint was all-cause mortality at one year. Cox regression models adjusting for the GRACE score (composite of age, heart rate systolic blood pressure, creatinine, cardiac arrest at admission, ST segment deviation, abnormal troponin enzyme and Killip classification), preexisting diabetes and inflammation (high-sensitivity C-reactive protein). A total of 430 men (40.8%) had total testosterone levels ≤300 ng/dL. Low total testosterone levels were correlated with lower high-density lipoprotein cholesterol and higher triglycerides, high-sensitivity C-reactive protein, high-sensitivity troponin T, N-terminal-pro B-type natriuretic peptide and glucose levels (all p < 0.01). Patients in the lowest testosterone tertile had a mortality rate at one-year of 5.4% compared with 2.9% in the highest tertile with an unadjusted hazard ratio of 1.92 (95% confidence interval 0.96-1.90, p = 0.095) and adjusted hazard ratio of 1.26 (95% confidence interval 0.57-2.78, p = 0.565). In an exploratory analysis, the highest mortality rate (10.3%) was observed in men aged >65 years old belonging to the lowest testosterone tertile.

Conclusion: In this large population of men with ACS, we found a prevalence of low total endogenous testosterone levels of almost 40%. However, low testosterone levels were not significantly associated with mortality after adjustment for high-risk confounders.
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http://dx.doi.org/10.1177/2047487319853343DOI Listing
April 2021

Eligibility for PCSK9 inhibitors based on the 2019 ESC/EAS and 2018 ACC/AHA guidelines.

Eur J Prev Cardiol 2021 03 20;28(1):59-65. Epub 2020 Jul 20.

Department of Cardiology, University Hospital Bern, Switzerland.

Aims: The 2018 American College of Cardiology (ACC)/American Heart Association (AHA) and 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) lipid guidelines recently updated their recommendations regarding proprotein convertase subtilisin/kexin-9 inhibitors (PCSK9i). We assessed the potential eligibility for PCSK9i according to the new guidelines in patients with acute coronary syndromes.

Methods And Results: We analysed a contemporary, prospective Swiss cohort of patients hospitalised for acute coronary syndromes. We modelled a statin intensification effect and an incremental ezetimibe effect on low-density lipoprotein-cholesterol levels among patients who were not on high-intensity statins or ezetimibe. One year after the index acute coronary syndrome event, treatment eligibility for PCSK9i was defined as low-density lipoprotein-cholesterol of 1.4 mmol/l or greater according to ESC/EAS guidelines. For ACC/AHA guidelines, treatment eligibility was defined as low-density lipoprotein-cholesterol of 1.8 mmol/l or greater in the presence of very high-risk atherosclerotic cardiovascular disease, defined by multiple major atherosclerotic cardiovascular disease events and/or high-risk conditions. Of 2521 patients, 93.2% were treated with statins (53% high-intensity statins) and 7.3% with ezetimibe at 1 year, and 54.9% had very high-risk atherosclerotic cardiovascular disease. Low-density lipoprotein-cholesterol levels less than 1.8 mmol/l and less than 1.4 mmol/l at 1 year were observed in 37.5% and 15.7% of patients, respectively. After modelling the statin intensification and ezetimibe effects, these numbers increased to 76.1% and 49%, respectively. The proportion of patients eligible for PCSK9i was 51% according to ESC/EAS criteria versus 14% according to ACC/AHA criteria.

Conclusions: In this analysis, the 2019 ESC/EAS guidelines rendered half of all post-acute coronary syndrome patients potentially eligible for PCSK9i treatment, as compared to a three-fold lower eligibility rate based on the 2018 ACC/AHA guidelines.
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http://dx.doi.org/10.1177/2047487320940102DOI Listing
March 2021

Prognostic value of inflammatory biomarkers and GRACE score for cardiac death and acute kidney injury after acute coronary syndromes.

Eur Heart J Acute Cardiovasc Care 2021 Feb 24. Epub 2021 Feb 24.

Department of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.

Aims : The aim of this study was to analyse the role of inflammation and established clinical scores in predicting acute kidney injury (AKI) after acute coronary syndromes (ACS).

Methods And Results : In a prospective multicentre cohort including 2034 patients with ACS undergoing percutaneous coronary intervention, high-sensitivity C-reactive protein (hsCRP), neutrophil count, neutrophil-to-lymphocyte ratio (NL-ratio), and creatinine were measured at the index procedure. AKI (n = 39, defined according to RIFLE criteria) and major cardiovascular and cerebrovascular events were adjudicated after 1 year. Associations between inflammation, AKI, and cardiac death (CD) were assessed by C-statistics and Cox proportional hazard models with log-rank test to compare survival. Patients with ACS with elevated neutrophil count >7.8 × 109/L, NL-ratio >5, combined neutrophil-count/creatinine, or NL-ratio/creatinine at baseline showed a higher incidence of AKI (all P < 0.05) and CD (all P < 0.001). The risk of AKI, CD, and their combination was increased in patients with higher neutrophil count/creatinine (heart rate (HR) = 3.7, 95% cardiac index (CI) 1.9-7.1; HR = 2.7, 95% CI 1.6-4.6; HR = 3.2, 95% CI 2.1-4.9); NL-ratio/creatinine (HR = 2.1, 95% CI 1.6-4.1; HR = 2.2, 95% CI 1.3-3.8; HR = 2.3, 95% CI 1.5-3.5); and hsCRP (HR = 1.8, 95% CI 0.9-3.5; HR = 2.2, 95% CI 1.3-3.6; HR = 1.9, 95% CI 1.2-2.8) after adjustment for age, diabetes, hypertension, previous heart failure, kidney function, haemodynamic instability at admission, statin, and renin-angiotensin-aldosterone antagonists use. Subjects with higher GRACE score 1.0/NL-ratio had higher rate of AKI, CD, and both (HR = 1.4, 95% CI 0.5-4.2; HR = 2.7, 95% CI 1.3-5.9; HR = 2.1, 95% CI 1-4.3).

Conclusions : Inflammation markers may predict AKI after correction for renal function at the index procedure. hsCRP performed better than the NL-ratio. However, the integration of inflammation markers to traditional risk factors or scores does not add prognostic information.

Trial Registration : ClinicalTrials.gov, NCT01000701.
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http://dx.doi.org/10.1093/ehjacc/zuab003DOI Listing
February 2021

Residual inflammatory risk at 12 months after acute coronary syndromes is frequent and associated with combined adverse events.

Atherosclerosis 2021 03 18;320:31-37. Epub 2021 Jan 18.

Department of Cardiology, University Heart Center, University Hospital Zurich, Switzerland; Center for Molecular Cardiology, University of Zurich, Switzerland.

Background And Aims: Residual inflammatory risk (RIR) after acute coronary syndromes (ACS) may identify patients likely to benefit from anti-inflammatory therapies.

Methods: Patients from the Special Program University Medicine ACS cohort were divided into four groups according to level of hsCRP at baseline and after 12 months: persistently high RIR, increased RIR (first low, then high hsCRP), attenuated RIR (first high, then low hsCRP), or persistently low RIR. High RIR was defined as hsCRP ≥ 2 mg/L. An independently adjudicated incident of combined adverse events was defined as the composite of myocardial infarction, clinically indicated coronary revascularization or cerebrovascular events.

Results: Among 1209 patients with available hsCRP, clinical and demographic data, 295 (24.4%) patients had persistently high RIR (delta hsCRP median (IQR): 2.3 (-9.9; 0.3) (mg/L) and 72 (5.96%) patients had increased RIR (delta hsCRP median (IQR): +2.45 (1.2; 8.35) (mg/L). A total of 390 (32.26%) patients had attenuated RIR (delta hsCRP median (IQR): 3.55 (-10; -2) (mg/L) and 452 (37.38%) patients had persistently low RIR (delta hsCRP median (IQR): 0.2 (-0.6; 0.1) (mg/L). Of 90 combined adverse events, 31 (10.5%) occurred in the persistently high (multivariable adjusted OR: 1.71, (95% CI 1.08-2.7), p = 0.022) compared with the three other groups combined (increased RIR: 3 (4.2%), attenuated RIR 30 (7.7%), persistently low RIR 26 (5.8%).

Conclusions: Persistently elevated hsCRP after ACS is found in a quarter of patients with the highest risk of combined adverse events. This underlines the need to perform anti-inflammatory intervention trials in RIR patients.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.01.012DOI Listing
March 2021

Impact of malignancy on clinical outcomes in patients with acute coronary syndromes.

Int J Cardiol 2021 Apr 13;328:8-13. Epub 2020 Dec 13.

Department of Cardiology, University Heart Centre, Zurich, Switzerland.

Background: The impact of cancer on survival in patients with coronary artery disease has not been well defined. We designed the present study to explore the prevalence and prognostic influence of cancer in patients with acute coronary syndrome (ACS).

Methods: 2'132 patients with ACS were enrolled in the prospective, multicenter Special Program University Medicine ACS (SPUM-ACS) cohort. The primary endpoints of major cardiovascular and cerebrovascular events (MACCE) and death were independently adjudicated at 30-day and at one-year follow-up.

Results: Of the 2'132 ACS patients 7.74% (n = 165) had cancer. At 30-day, except for net adverse clinical events (NACE defined as MACCE plus major bleeding), outcomes did not differ significantly between the two groups. At one year, MACCE rate was higher in cancer than in non-cancer patients (21.8 vs. 12.2%, p < 0.001). Even after adjusting for covariates, one-year all-cause mortality was higher in cancer patients than in those without (30.3% vs. 11.9%; p < 0.0001) as was cardiovascular mortality (15.7% vs. 5.9%; p < 0.001) and revascularization (12.7% vs. 5.5%, p < 0.001). Net adverse clinical events were also higher in patients with cancer at one-year follow-up (33.9% vs. 19.8%, p < 0.001). A sub-analysis revealed that those with solid tumors, but not hematological malignancies were more likely to experience MACCE (p = 0.001) as well as a higher cardiovascular and all cause mortality (both p = 0.001) at one-year follow-up.

Conclusions: ACS patients with cancer, specifically those with solid tumors, have a higher MACCE as well as cardiovascular and total mortality rate than non-cancer patients independent of cardiovascular risk factors. Thus, cancer is an independent risk factor for a poor outcome in ACS patients.
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http://dx.doi.org/10.1016/j.ijcard.2020.12.010DOI Listing
April 2021

Extracellular vesicle species differentially affect endothelial cell functions and differentially respond to exercise training in patients with chronic coronary syndromes.

Eur J Prev Cardiol 2020 May 7:2047487320919894. Epub 2020 May 7.

Department of Cardiology, Charité-Universitätsmedizin Berlin, Germany.

Background: Extracellular vesicles are released upon cellular activation and mediate inter-cellular communication. Individual species of extracellular vesicles might have divergent roles in vascular homeostasis and may show different responses to therapies such as exercise training.

Aims: We examine endothelial effects of medium-size and small extracellular vesicles from the same individual with or without chronic coronary syndrome, and in chronic coronary syndrome patients participating in a four-week high-intensity interval training intervention.

Methods: Human aortic endothelial cells were exposed to medium-size extracellular vesicles and small extracellular vesicles isolated from plasma samples of study participants. Endothelial cell survival, activation and re-endothelialisation capacity were assessed by respective staining protocols. Extracellular vesicles were quantified by nanoparticle tracking analysis and flow cytometry. Extracellular vesicle microRNA expression was quantified by realtime-quantitative polymerase chain reaction.

Results: In patients with chronic coronary syndrome ( = 25), plasma counts of leukocyte-derived medium-size extracellular vesicles were higher than in age-matched healthy controls ( = 25;  = 0.04) and were reduced by high-intensity interval training ( = 15;  = 0.01 vs baseline). Re-endothelialisation capacity was promoted by medium-size extracellular vesicles from controls, but not by medium-size extracellular vesicles from chronic coronary syndrome patients. High-intensity interval training for 4 weeks enhanced medium-size extracellular vesicle-mediated support of in vitro re-endothelialisation. Small extracellular vesicles from controls or chronic coronary syndrome patients increased endothelial cell death and reduced repair functions and were not affected by high-intensity interval training.

Conclusion: The present study demonstrates that medium-size extracellular vesicles and small extracellular vesicles differentially affect endothelial cell survival and repair responses. This equilibrium is unbalanced in patients with chronic coronary syndrome where leukocyte-derived medium-size extracellular vesicles are increased leading to a loss of medium-size extracellular vesicle-mediated endothelial repair. High-intensity interval training partially restored medium-size extracellular vesicle-mediated endothelial repair, underlining its use in cardiovascular prevention and therapy to improve endothelial function.
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http://dx.doi.org/10.1177/2047487320919894DOI Listing
May 2020

Optimal Timing of Invasive Coronary Angiography following NSTEMI.

J Interv Cardiol 2020 3;2020:8513257. Epub 2020 Mar 3.

Department of Cardiology, Lausanne University Center Hospital, Lausanne, Switzerland.

Objective: To obtain a real-world perspective of the optimal timing of angiography performed within 24 hours of admission with non-ST elevation myocardial infarction (NSTEMI).

Background: Current guidelines recommend angiography within 24 hours of hospitalisation with NSTEMI. The recent VERDICT trial found that angiography within 12 hours of admission with NSTEMI was associated with improved cardiovascular outcomes among high-risk patients. We compared the outcomes of real-world NSTEMI patients undergoing angiography within 12 hours of admission with those of patients undergoing angiography 12 to 24 hours after admission.

Methods: NSTEMI patients without life-threatening features who received angiography within 24 hours of admission were obtained from the SPUM-ACS registry, a cohort of consecutive patients admitted with acute coronary syndromes to four university hospitals in Switzerland. Cox models assessed for an association between door-to-catheter time and one-year major adverse cardiovascular events (MACE: cardiovascular mortality, myocardial infarction, and stroke).

Results: Of 2672 NSTEMI patients, 1832 met the inclusion criteria. Among them, 1464 patients underwent angiography within 12 hours (12 h group) compared with 368 patients between 12 and 24 hours (12-24 h group). Multiple logistic regression identified out-of-hours admission as the only factor associated with delayed angiography. After 2 : 1 propensity score matching, 736 patients from the 12 h group and 368 patients from the 12-24 h group demonstrated no significant difference in rates of one-year MACE (7.7% vs. 7.3%, HR: 1.050, 95% CI 0.637-1.733, =0.847). Stratification by GRACE score (>140 vs. ≤140) found no significant reduction in MACE among high-risk patients in the 12 h group (=0.847). Stratification by GRACE score (>140 vs. ≤140) found no significant reduction in MACE among high-risk patients in the 12 h group (.

Conclusions: In an unselected real-world cohort of NSTEMI patients, angiography within 12 hours of admission was not associated with improved one-year cardiovascular outcomes when compared with angiography 12 and 24 hours after admission, even among high-risk patients.
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http://dx.doi.org/10.1155/2020/8513257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073472PMC
September 2020

Intensified lipid lowering using ezetimibe after publication of the IMPROVE-IT trial: A contemporary analysis from the SPUM-ACS cohort.

Int J Cardiol 2020 03 10;303:8-13. Epub 2019 Dec 10.

Cardiology Division, Geneva University Hospitals, Switzerland.

Background: The relevance of the IMPROVE-IT trial on real-life practice has not been explored in patients with ACS.

Methods: A prospective Swiss cohort of 6266 patients hospitalized for ACS between 2009 and 2017 with a one-year follow-up. The primary endpoints were the ezetimibe use overall or in combination with high-intensity statin at discharge and at one year after ACS. Secondary endpoint was LDL-C target achievement at one year in a subsample of 2984 patients. Relative Ratios (RR) were used to assess changes in primary endpoints before and after the publication of IMPROVE-IT, adjusting for age, sex, diabetes, prior myocardial infarction, LDL-C and attendance to cardiac rehabilitation.

Results: The period following the publication of the IMPROVE-IT trial was associated with a steady increase in the use of ezetimibe at discharge (from 1.8% to 3.8%, P < 0.001, adjusted RR 2.85, 95% CI 1.90-4.25) and at one year (from 5.0% to 13.8%, P < 0.001, adjusted RR 3.00, 95% CI 2.40-3.75). The combination of high-intensity statin and ezetimibe rose from 0.9% to 2.1% at discharge (P < 0.001, adjusted RR 3.35, 95% CI 1.90-5.89) and from 2.1% to 7.8% at one year (P < 0.001, adjusted RR 3.98, 95% CI 2.90-5.47). The period following the publication of the IMPROVE-IT trial was associated with an improvement of LDL-C target <1.8 mmol/L (adjusted RR 1.37, 95% CI 1.12-1.68).

Conclusions: After the publication of the IMPROVE-IT trial, the use of ezetimibe was increased by three-fold in a large contemporary cohort of ACS patients, concomitant with an improved LDL-C target achievement.
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http://dx.doi.org/10.1016/j.ijcard.2019.12.011DOI Listing
March 2020

Prognosis of Patients with Chronic and Hospital-Acquired Anaemia After Acute Coronary Syndromes.

J Cardiovasc Transl Res 2020 08 25;13(4):618-628. Epub 2019 Nov 25.

Department of Cardiology, Lausanne University Center Hospital, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland.

Discharge anaemia is common following acute coronary syndromes (ACS). However, it is unknown if chronic anaemia (CA) and hospital-acquired anaemia (HAA) are associated with similar outcomes. In this retrospective analysis of 4083 ACS admissions treated with percutaneous coronary intervention in Switzerland (SPUM-ACS registry), 1896 patients (46.4%) had discharge anaemia (CA: n = 643 (15.7%) vs. HAA: n = 1253 (30.7%)). Landmark analysis that matched patients with CA (n = 504) and HAA (n = 866) with non-anaemic patients found increased 1-year major adverse cardiovascular events (cardiovascular mortality, myocardial infarction, stroke) among patients with CA (6.9% vs. 3.0%, HR 2.073, 95% CI 1.039-4.134, p = 0.039) and HAA (3.8% vs. 2.3%, HR 1.772, 95% CI 1.002-3.232, p = 0.049). Only CA was associated with increased 1-year all-cause mortality (7.9% vs. 1.6%, HR 4.255, 95% CI 1.950-9.284, p < 0.001). CA and HAA were associated with poor 1-year cardiovascular outcomes. Only CA was associated with increased all-cause mortality suggesting that HAA and CA represent distinct subclinical entities.
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http://dx.doi.org/10.1007/s12265-019-09934-wDOI Listing
August 2020

Diabetes and baseline glucose are associated with inflammation, left ventricular function and short- and long-term outcome in acute coronary syndromes: role of the novel biomarker Cyr 61.

Cardiovasc Diabetol 2019 10 31;18(1):142. Epub 2019 Oct 31.

Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland.

Background: Hyperglycemia in the setting of an acute coronary syndrome (ACS) impacts short term outcomes, but little is known about longer term effects. We therefore designed this study to firstly determine the association between hyperglycemia and short term and longer term outcomes in patients presenting with ACS and secondly evaluate the prognostic role of diabetes, body mass index (BMI) and the novel biomarker Cyr61 on outcomes.

Methods: The prospective Special Program University Medicine-Acute Coronary Syndrome (SPUM-ACS) cohort enrolled 2168 patients with ACS between December 2009 and October 2012, of which 2034 underwent PCI (93.8%). Patients were followed up for 12 months. Events were independently adjudicated by three experienced cardiologists. Participants were recruited from four tertiary hospitals in Switzerland: Zurich, Geneva, Lausanne and Bern. Participants presenting with acute coronary syndromes and who underwent coronary angiography were included in the analysis. Patients were grouped according to history of diabetes (or HbA1c greater than 6%), baseline blood sugar level (BSL; < 6, 6-11.1 and > 11.1 mmol/L) and body mass index (BMI). The primary outcome was major adverse cardiac events (MACE) which was a composite of myocardial infarction, stroke and all-cause death. Secondary outcomes included the individual components of the primary endpoint, revascularisations, bleeding events (BARC classification) and cerebrovascular events (ischaemic or haemorrhagic stroke or TIA).

Results: Patients with hyperglycemia, i.e. BSL ≥ 11.1 mmol/L, had higher levels of C-reactive protein (CRP), white blood cell count (WBC), creatinine kinase (CK), higher heart rates and lower left ventricular ejection fraction (LVEF) and increased N-terminal pro-brain natriuretic peptide. At 30 days and 12 months, those with BSL ≥ 11.1 mmol/L had more MACE and death compared to those with BSL < 6.0 mmol/L or 6.0-11.1 mmol/L (HR-ratio 4.78 and 6.6; p < 0.001). The novel biomarker Cyr61 strongly associated with high BSL and STEMI and was independently associated with 1 year outcomes (HR 2.22; 95% CI 1.33-3.72; Tertile 3 vs. Tertile 1).

Conclusions And Relevance: In this large, prospective, independently adjudicated cohort of in all comers ACS patients undergoing PCI, both a history of diabetes and elevated entry glucose was associated with inflammation and increased risk of MACE both at short and long-term. The mediators might involve increased sympathetic activation, inflammation and ischemia as reflected by elevated Cyr61 levels leading to larger levels of troponin and lower LVEF. Trial registration Clinical Trial Registration Number: NCT01000701. Registered October 23, 2009.
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http://dx.doi.org/10.1186/s12933-019-0946-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824030PMC
October 2019

Control of cardiovascular risk factors and health behaviors in patients post acute coronary syndromes eligible for protein convertase subtilisin/kexin-9 inhibitors.

Int J Cardiol 2020 01 9;299:289-295. Epub 2019 Oct 9.

Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland.

Background: We aimed to examine cardiovascular risk factors and health behaviors in patients with acute coronary syndromes (ACS) according to potential extension of eligibility criteria for protein convertase subtilisin/kexin-9 inhibitors (PCSK9i) to all patients with low-density lipoprotein cholesterol (LDL-c) equal or above 1.8 mmol/l.

Methods: In this prospective cross-sectional study, patients with ACS between 2009 and 2016 and with available LDL-c at one year were considered. We defined three mutually exclusive groups of patients according to eligibility for PCSK9i: "not eligible", "currently eligible", and "newly eligible". We explored the control of cardiovascular risk factors and health behaviors.

Results: Out of 3025 patients who had an ACS one year ago, 1071 (35.4%) were not eligible for PCSK9i, 415 (13.7%) were currently eligible, and 1539 (50.9%) were newly eligible. The proportion of patients with uncontrolled hypertension in the not eligible group was lower than in the group currently eligible (27.6% vs 33.6%, p = 0.02), but similar to the group newly eligible (27.6% vs 28.2%, p = 0.73). The proportion of smokers in the not eligible group was lower than in the group currently eligible (21.2% vs 28.0%, p = 0.02), but similar to the group newly eligible (21.2% vs 22.5%, p = 0.51).

Conclusions: More than half of patients with ACS would be additionally eligible for PCSK9i if prescription is extended from current guidelines to all patients with LDL-c equal or above 1.8 mmol/l. Patients currently eligible for PCSK9i one year after an ACS had a worst control of cardiovascular risk factors than patients potentially newly eligible.
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http://dx.doi.org/10.1016/j.ijcard.2019.10.012DOI Listing
January 2020

Non-Linear Relationship between Anti-Apolipoprotein A-1 IgGs and Cardiovascular Outcomes in Patients with Acute Coronary Syndromes.

J Clin Med 2019 Jul 9;8(7). Epub 2019 Jul 9.

Division of Cardiology, Cardiology Center, Geneva University Hospital, 1205 Geneva Switzerland.

Autoantibodies against apolipoprotein A-I (anti-apoA-I IgGs) are prevalent in atherosclerosis-related conditions. It remains elusive whether they improve the prognostic accuracy of the Global Registry of Acute Coronary Events (GRACE) score 2.0 (GS) in acute coronary syndromes (ACS). In this prospective multicenter registry, 1713 ACS patients were included and followed for 1 year. The primary endpoint (major adverse cardiovascular events (MACE)) was defined as the composite of myocardial infarction, stroke (including transient ischemic attack), or cardiovascular (CV) death with individual events independently adjudicated. Plasma levels of anti-apoA-I IgGs upon study inclusion were assessed using ELISA. The association between anti-apoA-I IgGs and incident MACE was assessed using Cox models with splines and C-statistics. One-year MACE incidence was 8.4% (144/1713). Anti-apoA-I IgG levels were associated with MACE with a non-linear relationship ( = 0.01), which remained unchanged after adjusting for the GS ( = 0.04). The hazard increased progressively across the two first anti-apoA-I IgG quartiles before decreasing thereafter. Anti-apoA-I IgGs marginally improved the prognostic accuracy of the GS (c-statistics increased from 0.68 to 0.70). In this multicenter study, anti-apoA-I IgGs were predictive of incident MACE in ACS independently of the GS but in a nonlinear manner. The practical implications of these findings remain to be defined.
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http://dx.doi.org/10.3390/jcm8071002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679072PMC
July 2019

Risk stratification of elderly patients with acute pulmonary embolism.

Eur J Clin Invest 2019 Sep 16;49(9):e13154. Epub 2019 Jul 16.

Department of Cardiology, University Heart Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background: Combining high-sensitivity cardiac Troponin T (hs-cTnT), NT-pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) may improve risk stratification of patients with pulmonary embolism (PE) beyond the PESI risk score.

Methods: In the prospective multicentre SWITCO65+ study, we analysed 214 patients ≥ 65 years with a new submassive PE. Biomarkers and clinical information for the PESI risk score were ascertained within 1 day after diagnosis. Associations of hs-TnT, NT-proBNP, hs-CRP and the PESI risk score with the primary endpoint defined as 6-month mortality were assessed. The discriminative power of the PESI risk score and its combination with hs-cTnT, NT-proBNP and hs-CRP for 6-month mortality was compared using integrated discrimination improvement (IDI) index and net reclassification improvement (NRI).

Results: Compared with the lowest quartile, patients in the highest quartile had a higher risk of death during the first 6 months for hs-cTnT (adjusted HR 10.22; 95% CI 1.79-58.34; P = 0.009) and a trend for NT-proBNP (adjusted HR 4.3; 95% CI 0.9-20.41; P = 0.067) unlike hs-CRP (adjusted HR 1.97; 95% CI 0.48-8.05; P = 0.344). The PESI risk score (c-statistic 0.77 (95% CI 0.69-0.84) had the highest prognostic accuracy for 6-month mortality, outperforming hs-cTnT, NT-proBNP and hs-CRP (c-statistics of 0.72, 0.72, and 0.54), respectively. Combining all three biomarkers had no clinically relevant impact on risk stratification when added to the PESI risk score (IDI = 0.067; 95% CI 0.012-0.123; P = 0.018; NRI = 0.101 95% CI -0.099-0.302; P = 0.321).

Conclusions: In elderly patients with PE, 6-month mortality can adequately be predicted by the PESI risk score alone.
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http://dx.doi.org/10.1111/eci.13154DOI Listing
September 2019

Sarcoma of the pulmonary artery mimicking pulmonary artery embolism.

Eur Heart J 2019 09;40(33):2824

Department of Cardiology, Kerckhoff Heart and Thorax Center, Benekestraße 2-8, D Bad Nauheim, Germany.

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http://dx.doi.org/10.1093/eurheartj/ehz288DOI Listing
September 2019

Inflammation during acute coronary syndromes - Risk of cardiovascular events and bleeding.

Int J Cardiol 2019 07 27;287:13-18. Epub 2019 Mar 27.

Department of Cardiology, University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Background: Many parameters can affect the level of inflammation during acute coronary syndromes (ACS). We aimed to assess the one-year risk of major adverse cardiovascular events (MACE) and bleeding associated with elevated hsCRP levels during ACS, taking into account the severity of myocardial infarction, the timing of blood sampling and established long-term prognostic factors.

Methods: We studied 1864 consecutive patients with ACS enrolled in a contemporary multicenter prospective cohort study in Switzerland. HsCRP levels were determined at hospital admission. One year after discharge MACE and bleeding events were assessed. Multivariable adjusted Cox proportional hazards were computed with age, sex, time from symptom onset to blood draw, body mass index, current smoking, hypertension, diabetes mellitus, pre-existing cardiovascular disease, history of inflammatory disease, LDL-cholesterol levels, type of ACS, left ventricular ejection fraction and GRACE 1.0 risk score.

Results: At one-year follow-up, 151 (8.1%) patients suffered MACE. Compared to patients with hsCRP below 2 mg/l, the risk of MACE was higher in patients with hsCRP levels between 2 and 5 mg/l, with a multivariate adjusted hazard ratio (HR) of 1.63 (95% confidence interval (CI) 0.93-2.84), in those with levels between 5 and 10 mg/l, with a HR of 2.80 (95% CI 1.58-4.96), and in those with levels above 10 mg/l, with a HR of 2.23 (95% CI 1.28-3.88). There was no difference in bleeding risk between the four groups.

Conclusions: Systemic inflammation in the acute phase of myocardial infarction is an independent predictor for cardiovascular events, but not for bleeding.
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http://dx.doi.org/10.1016/j.ijcard.2019.03.049DOI Listing
July 2019

Prognostic value of elevated lipoprotein(a) in patients with acute coronary syndromes.

Eur J Clin Invest 2019 Jul 7;49(7):e13117. Epub 2019 May 7.

Cardiology Division, Geneva University Hospitals, Geneva, Switzerland.

Background: Minimal lipoprotein(a) [Lp(a)] target values are advocated for high-risk cardiovascular patients. We investigated the prognostic value of Lp(a) in the acute setting of patients with acute coronary syndromes (ACS).

Materials And Methods: Plasma levels of Lp(a) were collected at time of angiography from 1711 patients hospitalized for ACS in a multicentre Swiss prospective cohort. Associations between elevated Lp(a) ≥30 mg/dL (cut-off corresponding to the 75th percentile of the assay) or Lp(a) tertiles at baseline, and major adverse cardiovascular events (MACE) at 1 year, defined as a composite of cardiac death, myocardial infarction or stroke, were assessed using hazard ratios (HR) and 95% confidence intervals (CI) adjusting for traditional cardiovascular risk factors (age, sex, smoking, diabetes, hypertension, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C] and triglycerides.

Results: Lp(a) levels range between 2.5 and 132 mg/dL with a median value of 6 mg/dL and a mean value of 14.2 mg/dL. A total of 276 patients (23.0%) had Lp(a) plasma levels ≥30 mg/dL. Patients with elevated Lp(a) were more likely to be of female gender and to have higher levels of total cholesterol, LDL-C, HDL-C and triglycerides. Higher Lp(a) was associated with failure to reach the LDL-C target <1.8 mmol/L at 1 year (HR 1.71, 95% CI 1.13-2.58, P = 0.01). No association was found between elevated Lp(a) and MACE at 1 year (HR 1.05, 95% CI 0.64-1.73), nor for Lp(a) tertiles (HR 0.82, 95% CI 0.52-1.28, P > 0.20) or standardized continuous variables (0.98, 95% CI 0.82-1.19 for each increase of standard deviation).

Conclusions: Our real-world data suggest high Lp(a) levels at time of angiography are not predictive for cardiovascular outcomes in patients otherwise medically well controlled, but might be useful to identify patients who would not be on LDL-C targets 1 year after ACS.
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http://dx.doi.org/10.1111/eci.13117DOI Listing
July 2019

Clinical impact of a structured secondary cardiovascular prevention program following acute coronary syndromes: A prospective multicenter healthcare intervention.

PLoS One 2019 21;14(2):e0211464. Epub 2019 Feb 21.

Cardiology Division, Geneva University Hospitals, Geneva, Switzerland.

Background: Structured secondary cardiovascular prevention programs (SSCP) following acute coronary syndromes (ACS) may reduce major adverse cardiovascular events (MACE) through better adherence to post-ACS recommendations.

Methods: Through a prospective multicenter cohort study, we compared the outcomes of two sequential post-ACS patient cohorts, the initial one receiving standard care (SC) followed by one receiving additional interventions (SSCP) aimed at improving patient education as well as healthcare provider and hospital systems. The primary endpoint was MACE at one year. Secondary endpoints included adherence to recommended therapies, attendance to cardiac rehabilitation (CR) and successful achievement of cardiovascular risk factor (CVRF) targets.

Results: In total, 2498 post-ACS patients from 4 Swiss university hospitals were included: 1210 vs 1288 in the SC and SSCP groups, respectively. The SSCP group demonstrated a significant increase in attendance to CR programs (RR 1.08, 95%CI 1.02-1.14, P = 0.006), despite not achieving the primary MACE endpoint (HR 0.97, 95%CI 0.77-1.22, P = 0.79). After age-stratification, significant reductions in cardiac death, MI and stroke events (HR 0.53, 95%CI 0.30-0.93, P for interaction = 0.016) were observed for SSCP patients ≤ 65 years old. The SSCP group also scored significantly better for the LDL cholesterol target (RR 1.07, 95%CI 1.02-1.13, P = 0.012), systolic blood pressure target (RR 1.06, 95%CI 1.01-1.13, P = 0.029) and physical activity (RR 1.10, 95%CI 1.01-1.20, P = 0.021).

Conclusions: The implementation of an SSCP post ACS was associated with an improvement in the control of CVRF and attendance to CR programs, and was also associated with significant reductions in cardiac death, MI and stroke at one year for patients ≤65years old.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211464PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383891PMC
November 2019

Prognostic Value of SYNTAX Score II in Patients with Acute Coronary Syndromes Referred for Invasive Management: A Subanalysis from the SPUM and COMFORTABLE AMI Cohorts.

Cardiol Res Pract 2018 25;2018:9762176. Epub 2018 Sep 25.

Royal Brompton & Harefield Hospital Trust, Imperial College London, London, UK.

Aims: To assess the incremental prognostic value of SYNTAX score II (SxSII) as compared to anatomical SYNTAX Score (SxS) and GRACE risk score in patients with acute coronary syndromes who underwent percutaneous coronary intervention.

Methods And Results: SxSII and SxS were determined in 734 ACS patients. Patients were enrolled in the prospective Special Program University Medicine ACS and the COMFORTABLE AMI cohorts and later on stratified according to tertiles of SxSII (SxSII ≤21.5 (=245), SxSII 21.5-30.6 (=245), and SxSII ≥30.6 (=244). The primary endpoint of adjudicated all-cause mortality and secondary endpoints of MACE (cardiac death, repeat revascularization, and myocardial infarction) and MACCE (all-cause mortality, cerebrovascular events, MI, and repeat revascularization) were determined at 1-year follow-up. SxSII provided incremental predictive information for risk stratification when compared to SxS and GRACE risk score (AUC 0.804, 95% CI 0.77-0.84, < 0.001 versus 0.67, 95% CI 0.63-0.72, =0.007 versus 0.69, 95% CI 0.6-0.8, =0.002), respectively. In a multivariable Cox regression analysis, we found that unlike SxS (adjusted HR 1.013, 95% CI (0.96-1.07), =0.654), SxSII was significantly associated with all-cause mortality (HR = 1.095, 95% CI (1.06-1.11), < 0.001). This was also true for the prediction of both secondary outcomes MACE (=60) and MACCE (=70) with an adjusted HR = 1.055, 95% CI (1.03-1.08), < 0.001, and HR = 1.065, 95% CI (1.04-1.09), < 0.001.

Conclusion: In patients with ACS who underwent PCI, SxSII is an independent predictor of mortality during 1-year follow-up. SxSII shows superiority in discriminating risk compared to conventional SxS and GRACE for all-cause mortality.
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http://dx.doi.org/10.1155/2018/9762176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176297PMC
September 2018

Gender and age differences in outcomes of patients with acute coronary syndromes referred for coronary angiography.

Catheter Cardiovasc Interv 2019 01 5;93(1):16-24. Epub 2018 Oct 5.

Department of Cardiology, University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Objectives: The number of elderly patients undergoing coronary revascularization is steadily increasing, and data on the impact of gender on outcomes are scarce. This study sought to assess gender-related differences in outcomes in elderly patients with acute coronary syndromes (ACS).

Methods: We investigated outcomes in elderly ACS patients referred for coronary angiography and prospectively enrolled in the Swiss ACS Cohort between December 2009 and October 2012. Adjudicated major adverse cardiovascular and cerebrovascular events (MACCE) included all-cause death, non-fatal myocardial infarction, clinically indicated repeat coronary revascularization, definite stent thrombosis, and transient ischemic attack/stroke.

Results: Among 2,168 patients recruited, 481 (22%) patients were >75 years of age (37% women). In patients >75 years, 1-year MACCE rates were 15% and 23% in women and men (OR 0.59, 95% CI 0.36-0.97, P = 0.04), respectively, and differences remained significant after adjustments for baseline variables (adjusted OR 0.48, 95% CI 0.26-0.90, P = 0.02). Women >75 years had a lower cardiovascular mortality (6% versus 12%, adjusted OR 0.31, 95% CI 0.12-0.81, P = 0.02). In patients ≤75 years, 1-year MACCE rates did not differ between gender (10% and 8% for women and men, adjusted OR 1.28, 95% CI 0.77-2.14, P = 0.34). Rates of TIMI major bleeding for women and men were 4% and 4% in patients >75 years (P = 0.96), and 5% and 3% in those ≤75 years (P = 0.11).

Conclusions: The low rates of MACCE observed in elderly women in this patient cohort suggest that with current interventional strategies the gender gap in ACS management has been attenuated.
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http://dx.doi.org/10.1002/ccd.27712DOI Listing
January 2019

CANTOS: a seductive song with several verses.

Eur Heart J 2018 10;39(38):3508-3510

Department of Cardiology, Kerckhoff Heart and Thorax Center, Kerckhoff-Klinik, Bad Nauheim, Germany and Department of Cardiology, Royal Brompton and Harefield Hospitals and Imperial College, London, UK.

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http://dx.doi.org/10.1093/eurheartj/ehy363DOI Listing
October 2018

Prognostic value of pulse pressure after an acute coronary syndrome.

Atherosclerosis 2018 10 20;277:219-226. Epub 2018 Jul 20.

Service of Cardiology, Lausanne University Hospital, Lausanne, Switzerland. Electronic address:

Background And Aims: Pulse pressure (PP) is a surrogate of aortic stiffness (AS) easily obtainable. The link between AS and cardio-vascular disease is documented, however, data regarding acute coronary syndrome (ACS) patients are scarce and contradictory. We aimed to assess the prognostic value of PP measured at admission, with regard to major adverse outcomes (all-cause mortality, recurrence of MI, and stroke), during the first year following an acute coronary syndrome (ACS).

Methods: The SPUM-ACS project is a prospective cohort study of patients with ACS conducted in 4 Swiss University hospitals. Patients with no PP at admission or with severe clinical heart failure or cardiogenic shock were excluded. Cox regression analyses were performed to determine associations between PP and outcomes (all-cause mortality, recurrence of myocardial infarction (MI), and stroke). Three multivariate Cox regression models were adjusted for hemodynamic, cardiovascular, and non-cardiovascular confounders, added successively.

Results: Of 5635 eligible patients, 5070 met the inclusion criteria. Mean patient age was 63 years (range: 54-72), 79.6% were male, and mean blood pressure and PP were 93.9 ± 15.6 and 54 ± 17 mmHg, respectively. Multivariate analyses confirmed the prognostic significance of PP for each 10-mmHg increase for the composite endpoint, hazard ratio (HR) 1.126 [1.051-1.206], p = 0.001; all-cause mortality, HR1.129 [1.013-1.260], p = 0.029; and recurrence of MI, HR1.206 [1.102-1.320], p < 0.001; but not for stroke, HR1.014[0.853-1.205].

Conclusions: PP measured at admission is a strong, independent prognostic marker predicting mortality and recurrence of MI after ACS. PP should be considered for the management of secondary prevention.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.07.013DOI Listing
October 2018

Predictive value of the age, creatinine, and ejection fraction (ACEF) score in patients with acute coronary syndromes.

Int J Cardiol 2018 Nov 1;270:7-13. Epub 2018 Jun 1.

Department of Cardiology, University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Background: This study sought to investigate the predictive value of the age, creatinine, and ejection fraction (ACEF) score in patients with acute coronary syndromes (ACS). The ACEF score (age/left ventricular ejection fraction +1 [if creatinine > 176 μmol/L]) has been established in patients evaluated for coronary artery bypass surgery. Data on its predictive value in all-comer ACS patients undergoing percutaneous coronary intervention are scarce.

Methods: A total of 1901 patients prospectively enrolled in the Swiss ACS Cohort were included in the analysis. Optimal ACEF score cut-off values were calculated by decision tree analysis, and patients divided into low-risk (≤1.45), intermediate-risk (>1.45 and ≤2.0), and high-risk groups (>2.0). The primary endpoint was all-cause mortality. Major adverse cardiac and cerebrovascular events (MACCE) included all-cause death, non-fatal myocardial infarction, clinically indicated repeat coronary revascularization, definite stent thrombosis, and transient ischemic attack/stroke.

Results: One-year rates of all-cause death increased across ACEF score groups (1.6% versus 5.6% versus 23.0%, p < 0.001). In multivariate analysis, the ACEF score was related with an increased risk of all-cause mortality (adjusted HR 3.53, 95% CI 2.90-4.31, p < 0.001), MACCE (adjusted HR 2.23, 95% CI 1.88-2.65, p < 0.001), and transient ischemic attack/stroke (adjusted HR 2.58, 95% CI 1.71-3.89, p < 0.001) at 1 year. Rates of Thrombolysis in Myocardial Infarction (TIMI) major and Global use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe bleeding paralleled the increased ischemic risk across the groups (p < 0.001).

Conclusions: The ACEF score is a simple and useful risk stratification tool in patients with ACS referred for coronary revascularization.
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http://dx.doi.org/10.1016/j.ijcard.2018.05.134DOI Listing
November 2018

Prognostic values of fasting hyperglycaemia in non-diabetic patients with acute coronary syndrome: A prospective cohort study.

Eur Heart J Acute Cardiovasc Care 2020 Sep 4;9(6):589-598. Epub 2018 Jun 4.

Cardiology Division, Geneva University Hospitals, Switzerland.

Background: Controversy remains regarding the prevalence of hyperglycaemia in non-diabetic patients hospitalised with acute coronary syndrome and its prognostic value for long-term outcomes.

Methods And Results: We evaluated the prevalence of hyperglycaemia (defined as fasting glycaemia ⩾10 mmol/l) among patients with no known diabetes at the time of enrolment in the prospective Special Program University Medicine-Acute Coronary Syndromes cohort, as well as its impact on all-cause death, myocardial infarction, stroke and incidence of diabetes at one year. Among 3858 acute coronary syndrome patients enrolled between December 2009-December 2014, 709 (18.4%) had known diabetes, while 112 (3.6%) of non-diabetic patients had hyperglycaemia at admission. Compared with non-hyperglycaemic patients, hyperglycaemic individuals were more likely to present with ST-elevation myocardial infarction and acute heart failure. At discharge, hyperglycaemic patients were more frequently treated with glucose-lowering agents (8.9% vs 0.66%, <0.001). At one-year, adjudicated all-cause death was significantly higher in non-diabetic patients presenting with hyperglycaemia compared with patients with no hyperglycaemia (5.4% vs 2.2%, =0.041) and hyperglycaemia was a significant predictor of one-year mortality (adjusted hazard ratio 2.39, 95% confidence interval 1.03-5.56). Among patients with hyperglycaemia, 9.8% had developed diabetes at one-year, while the corresponding proportion among patients without hyperglycaemia was 1.8% (<0.001). In multivariate analysis, hyperglycaemia at presentation predicted the onset of treated diabetes at one-year (odds ratio 4.15, 95% confidence interval 1.59-10.86; =0.004).

Conclusion: Among non-diabetic patients hospitalised with acute coronary syndrome, a fasting hyperglycaemia of ⩾10 mmol/l predicted one-year mortality and was associated with a four-fold increased risk of developing diabetes at one year.
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http://dx.doi.org/10.1177/2048872618777819DOI Listing
September 2020

Incidence, Predictors, and Clinical Impact of Early Prasugrel Cessation in Patients With ST-Elevation Myocardial Infarction.

J Am Heart Assoc 2018 04 13;7(8). Epub 2018 Apr 13.

Department of Cardiology, Bern University Hospital, Bern, Switzerland

Background: Early withdrawal of recommended antiplatelet treatment with clopidogrel adversely affects prognosis following percutaneous coronary interventions. Optimal antiplatelet treatment is essential following ST-segment elevation myocardial infarction (STEMI) given the increased risk of thrombotic complications. This study assessed the frequency, predictors, and clinical impact of early prasugrel cessation in patients with STEMI undergoing primary percutaneous coronary interventions.

Methods And Results: We pooled patients with STEMI discharged on prasugrel in 2 prospective registries (Bern PCI Registry [NCT02241291] and SPUM-ACS (Inflammation and Acute Coronary Syndromes) [NCT01000701]) and 1 STEMI trial (COMFORTABLE-AMI (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction) [NCT00962416]). Prasugrel treatment status at 1 year was categorized as no cessation; crossover to another P2Y-inhibitor; physician-recommended discontinuation; and disruption because of bleeding, side effects, or patient noncompliance. In time-dependent analyses, we assessed the impact of prasugrel cessation on the primary end point, a composite of cardiac death, myocardial infarction, and stroke. Of all 1830 included patients (17% women, mean age 59 years), 83% were treated with new-generation drug-eluting stents. At 1 year, any prasugrel cessation had occurred in 13.8% of patients including crossover (7.2%), discontinuation (3.7%), and disruption (2.9%). Independent predictors of any prasugrel cessation included female sex, age, and history of cerebrovascular event. The primary end point occurred in 5.2% of patients and was more frequent following disruption (hazard ratio 3.04, 95% confidence interval,1.34-6.91; =0.008), without significant impact of crossover or discontinuation. Consistent findings were observed for all-cause death, myocardial infarction, and stent thrombosis following prasugrel disruption.

Conclusions: In this contemporary study of patients with STEMI, early prasugrel cessation was not uncommon and primarily involved change to another P2Y-inhibitor. Disruption was the only type of early prasugrel cessation associated with statistically significant excess in ischemic risk within 1 year following primary percutaneous coronary interventions.
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http://dx.doi.org/10.1161/JAHA.117.008085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015438PMC
April 2018

Prognosis of cardiovascular and non-cardiovascular multimorbidity after acute coronary syndrome.

PLoS One 2018 12;13(4):e0195174. Epub 2018 Apr 12.

Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland.

Objective: To examine the prognosis of patients with cardiovascular and non-cardiovascular multimorbidity after acute coronary syndrome compared to patients without prior multimorbidity.

Methods: This multicenter prospective cohort study in Switzerland included 5,635 patients hospitalized with acute coronary syndrome between 2009 and 2014, with a one-year follow-up period. We defined cardiovascular and non-cardiovascular multimorbidity as having at least two prior comorbidities before the index hospitalization. Multivariable adjusted Cox proportional models were built to assess the one-year risk of recurrent cardiovascular events, defined as cardiovascular mortality and non-fatal myocardial infarction or stroke. The final model was adjusted for age, gender, body mass index, tobacco consumption, education, and family history of cardiovascular disease, prescription of high-dose statinsat discharge and use of cardiac rehabilitation after discharge.

Results: Overall, 3,664 patients (65%) had no multimorbidity, 1,839 (33%) had cardiovascular multimorbidity, 62 (1%) had non-cardiovascular multimorbidity, and 70 (1%) had both cardiovascular and non-cardiovascular multimorbidity. The multivariate risk of recurrent cardiovascular events was increased among patients with cardiovascular multimorbidity (hazard ratio (HR) 2.05, 95% CI: 1.54-2.73, p<0.001) and patients with non-cardiovascular multimorbidity (HR 2.57, 95% CI: 1.04-6.35, p = 0.04) compared to patients without multimorbidity. Patients with cardiovascular and non-cardiovascular multimorbidity had the highest risk of recurrence with a HR of 5.19, 95% CI: 2.79-9.64, p<0.001, compared to patients without multimorbidity.

Conclusions: Multimorbidity increased by two-fold the risk of cardiovascular events over the year after an acute coronary syndrome. The magnitude of this increased risk was similar for patients with cardiovascular or non-cardiovascular multimorbidity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195174PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896917PMC
July 2018

Loss of Sirt3 accelerates arterial thrombosis by increasing formation of neutrophil extracellular traps and plasma tissue factor activity.

Cardiovasc Res 2018 07;114(8):1178-1188

Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.

Aims: Sirtuin 3 (Sirt3) is a mitochondrial, nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that reduces oxidative stress by activation of superoxide dismutase 2 (SOD2). Oxidative stress enhances arterial thrombosis. This study investigated the effects of genetic Sirt3 deletion on arterial thrombosis in mice in an inflammatory setting and assessed the clinical relevance of these findings in patients with ST-elevation myocardial infarction (STEMI).

Methods And Results: Using a laser-induced carotid thrombosis model with lipopolysaccharide (LPS) challenge, in vivo time to thrombotic occlusion in Sirt3-/- mice (n = 6) was reduced by half compared to Sirt3+/+ wild-type (n = 8, P < 0.01) controls. Ex vivo analyses of whole blood using rotational thromboelastometry revealed accelerated clot formation and increased clot stability in Sirt3-/- compared to wild-type blood. rotational thromboelastometry of cell-depleted plasma showed accelerated clotting initiation in Sirt3-/- mice, whereas overall clot formation and firmness remained unaffected. Ex vivo LPS-induced neutrophil extracellular trap formation was increased in Sirt3-/- bone marrow-derived neutrophils. Plasma tissue factor (TF) levels and activity were elevated in Sirt3-/- mice, whereas plasma levels of other coagulation factors and TF expression in arterial walls remained unchanged. SOD2 expression in bone marrow -derived Sirt3-/- neutrophils was reduced. In STEMI patients, transcriptional levels of Sirt3 and its target SOD2 were lower in CD14+ leukocytes compared with healthy donors (n = 10 each, P < 0.01).

Conclusions: Sirt3 loss-of-function enhances experimental thrombosis in vivo via an increase of neutrophil extracellular traps and elevation of TF suggesting thrombo-protective effects of endogenous Sirt3. Acute coronary thrombosis in STEMI patients is associated with lower expression levels of SIRT3 and SOD2 in CD14+ leukocytes. Therefore, enhancing SIRT3 activity by pan-sirtuin activating NAD+-boosters may provide a novel therapeutic target to prevent or treat thrombotic arterial occlusion in myocardial infarction or stroke.
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http://dx.doi.org/10.1093/cvr/cvy036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014146PMC
July 2018

Cysteine-rich angiogenic inducer 61 (Cyr61): a novel soluble biomarker of acute myocardial injury improves risk stratification after acute coronary syndromes.

Eur Heart J 2017 Dec;38(47):3493-3502

Department of Cardiology, University Heart Center, University Hospital of Zurich and Center for Molecular Cardiology, University of Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland and Wagistr. 12, CH-8952 Schlieren, Switzerland.

Aims: We aimed to identify a novel biomarker involved in the early events leading to an acute coronary syndrome (ACS) and evaluate its role in diagnosis and risk stratification.

Methods And Results: Biomarker identification was based on gene expression profiling. In coronary thrombi of ACS patients, cysteine-rich angiogenic inducer 61 (Cyr61, CCN1) gene transcripts were highly up-regulated compared with peripheral mononuclear cells. In a murine ischaemia-reperfusion model (I/R), myocardial Cyr61 expression was markedly increased compared with the controls. Cyr61 levels were determined in human serum using an enzyme-linked immunosorbent assay. Cohorts of ACS (n = 2168) referred for coronary angiography, stable coronary artery disease (CAD) (n = 53), and hypertrophic obstructive cardiomyopathy (HOCM) patients (n = 15) served to identify and evaluate the diagnostic and prognostic performance of the biomarker. Cyr61 was markedly elevated in ST-elevation myocardial infarction patients compared with non-ST-elevation myocardial infarction/unstable angina or stable CAD patients, irrespective of whether coronary thrombi were present. Cyr61 was rapidly released after occlusion of a septal branch in HOCM patients undergoing transcoronary ablation of septal hypertrophy. Cyr61 improved risk stratification for all-cause mortality when added to the reference GRACE risk score at 30 days (C-statistic 0.88 to 0.89, P = 0.001) and 1 year (C-statistic 0.77 to 0.80, P < 0.001) comparable to high-sensitivity troponin T (30 days: 0.88 to 0.89, P < 0.001; 1 year: 0.77 to 0.79, P < 0.001). Similar results were obtained for the composite endpoint of all-cause mortality or myocardial infarction. Conversely, in a population-based case-control cohort (n = 362), Cyr61 was not associated with adverse outcome.

Conclusion: Cyr61 is a novel early biomarker reflecting myocardial injury that improves risk stratification in ACS patients.
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http://dx.doi.org/10.1093/eurheartj/ehx640DOI Listing
December 2017

Eligibility for PCSK9 Inhibitors According to American College of Cardiology (ACC) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) Guidelines After Acute Coronary Syndromes.

J Am Heart Assoc 2017 Nov 9;6(11). Epub 2017 Nov 9.

Department of Cardiology, University Hospital Bern, Switzerland.

Background: The American College of Cardiology (ACC) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) have recently published recommendations for the use of proprotein convertase subtilisin/kexin-9 (PCSK9) inhibitors in situations of very high risk. We aim to assess in the real world the suitability of PCSK9 inhibitors for acute coronary syndromes.

Methods And Results: We analyzed a prospective Swiss cohort of 2023 patients hospitalized for acute coronary syndromes between 2009 and 2014 with available data for low-density lipoprotein cholesterol and lipid-lowering therapy at 1 year. Clinical familial hypercholesterolemia was defined using the Dutch Lipid Clinic Network algorithm as unlikely, possible, probable, or definite. We simulated a fixed relative reduction of 24% in low-density lipoprotein cholesterol levels at 1 year in all patients not treated with ezetimibe, irrespective of the low-density lipoprotein cholesterol levels and statin regimen. At 1 year, 94.3% of patients were treated with statin, 5.8% with ezetimibe, and 35.8% of patients had on-target low-density lipoprotein cholesterol levels (<1.8 mmol/L); 25.6% met criteria for possible or probable/definite familial hypercholesterolemia. After a simulation of the lipid-lowering effect of ezetimibe, the proportion of patients who would be eligible for PCSK9 inhibitors at 1 year was 13.4% using American College of Cardiology criteria and 2.7% using European Society of Cardiology/European Atherosclerosis Society criteria. Patients with possible or probable/definite familial hypercholesterolemia were more eligible for PCSK9 inhibitors compared with their non-familial hypercholesterolemia counterparts: 27.6% versus 8.8% according to American College of Cardiology criteria and 6.6% versus 1.8% according to European Society of Cardiology/European Atherosclerosis Society criteria (<0.001).

Conclusions: Recommendations made by the American College of Cardiology guidelines would lead to 5-fold higher eligibility rates for PCSK9 inhibitors compared to the European Society of Cardiology/European Atherosclerosis Society consensus statement in acute coronary syndrome patients.
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http://dx.doi.org/10.1161/JAHA.117.006537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721754PMC
November 2017

Thrombus aspiration in acute coronary syndromes: prevalence, procedural success, change in serial troponin T levels and clinical outcomes in a contemporary Swiss cohort.

Eur Heart J Acute Cardiovasc Care 2018 Sep 20;7(6):522-531. Epub 2017 Apr 20.

3 Department of Cardiology, University Heart Center, University Hospital Zurich, Switzerland.

Background: Randomised controlled trials have provided conflicting results regarding procedural and clinical outcomes of thrombus aspiration combined with percutaneous coronary intervention, when compared with primary percutaneous coronary intervention alone in patients with acute coronary syndromes.

Methods: Acute coronary syndrome patients referred for coronary angiography to four Swiss university hospitals between 2009 and 2012 were enrolled in the SPUM-ACS cohort. At the discretion of the interventional cardiologist, patients underwent thrombus aspiration with percutaneous coronary intervention or percutaneous coronary intervention alone. Procedural success was defined as post-procedural thrombolysis in myocardial infarction III flow in the infarct-related artery. Serial changes in high-sensitivity troponin T (ΔhsTnT) and adjudicated 30 days (1 year) clinical events defined as the composite of cardiac death, recurrent myocardial infarction or clinically indicated coronary revascularisation were assessed.

Results: Among 1641 patients, 777 (47.4%) had angiographic evidence of coronary thrombus. Patients were categorised into thrombus aspiration with percutaneous coronary intervention ( n=663) or percutaneous coronary intervention alone ( n=114). ST-segment elevation myocardial infarction (STEMI) patients more often received thrombus aspiration with percutaneous coronary intervention (87.8%) than non-STEMI patients (73.5%), P<0.001. Procedural success was not different in thrombus aspiration with percutaneous coronary intervention compared with percutaneous coronary intervention alone (93.8% vs. 90.7%, P=0.243). ΔhsTnT was similar in STEMI patients (3.09±4.52 vs. 2.19±4.92 µg/l, P=0.086) as was clinical outcome in the entire cohort at 30 days (2.9% vs. 3.6%, P=0.76) and 1 year (7.2% vs. 5.3%, P=0.55) regardless of whether thrombus aspiration was used during primary percutaneous coronary intervention or not.

Conclusions: In this real-world acute coronary syndrome cohort, patients treated by thrombus aspiration with percutaneous coronary intervention showed no difference in the restoration of coronary blood flow compared with percutaneous coronary intervention alone immediately after the procedure. Furthermore, ΔhsTnT and clinical outcomes at either 30 days or 1 year were similar between thrombus aspiration with percutaneous coronary intervention or percutaneous coronary intervention alone.

Clinical Trials Registration: SPUM-ACS cohort NCT01000701.
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http://dx.doi.org/10.1177/2048872617706480DOI Listing
September 2018

Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors.

Eur Heart J 2017 Mar;38(11):814-824

Department of Cardiology, University Heart Center, University Hospital Zurich, Switzerland.

Aims: Systemic levels of trimethylamine N-oxide (TMAO), a pro-atherogenic and pro-thrombotic metabolite produced from gut microbiota metabolism of dietary trimethylamine (TMA)-containing nutrients such as choline or carnitine, predict incident cardiovascular event risks in stable primary and secondary prevention subjects. However, the prognostic value of TMAO in the setting of acute coronary syndromes (ACS) remains unknown.

Methods And Results: We investigated the relationship of TMAO levels with incident cardiovascular risks among sequential patients presenting with ACS in two independent cohorts. In the Cleveland Cohort, comprised of sequential subjects (n = 530) presenting to the Emergency Department (ED) with chest pain of suspected cardiac origin, an elevated plasma TMAO level at presentation was independently associated with risk of major adverse cardiac events (MACE, including myocardial infarction, stroke, need for revascularization, or death) over the ensuing 30-day (4th quartile (Q4) adjusted odds ratio (OR) 6.30, 95% confidence interval (CI), 1.89-21.0, P < 0.01) and 6-month (Q4 adjusted OR 5.65, 95%CI, 1.91-16.7; P < 0.01) intervals. TMAO levels were also a significant predictor of the long term (7-year) mortality (Q4 adjusted HR 1.81, 95%CI, 1.04-3.15; P < 0.05). Interestingly, TMAO level at initial presentation predicted risk of incident MACE over the near-term (30 days and 6 months) even among subjects who were initially negative for troponin T (< 0.1 ng/mL) (30 days, Q4 adjusted OR 5.83, 95%CI, 1.79-19.03; P < 0.01). The prognostic value of TMAO was also assessed in an independent multicentre Swiss Cohort of ACS patients (n = 1683) who underwent coronary angiography. Trimethylamine N-oxide again predicted enhanced MACE risk (1-year) (adjusted Q4 hazard ratios: 1.57, 95% CI, 1.03-2.41; P <0.05).

Conclusion: Plasma TMAO levels among patients presenting with chest pain predict both near- and long-term risks of incident cardiovascular events, and may thus provide clinical utility in risk stratification among subjects presenting with suspected ACS.
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http://dx.doi.org/10.1093/eurheartj/ehw582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837488PMC
March 2017