Publications by authors named "Philipp Jakob"

23 Publications

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Impact of renal function on outcomes of patients with cardiac troponin elevation and non-obstructive coronary arteries.

Int J Cardiol 2021 Feb 20. Epub 2021 Feb 20.

Department of Cardiology, Charité Berlin - University Medicine, Campus Benjamin Franklin, Berlin, Germany; Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany. Electronic address:

Background: Patients with signs and symptoms suggestive of myocardial infarction and non-obstructive coronary arteries are at increased risk of adverse events. The aim of this study was to investigate the predictive role of renal function in troponin-positive patients with non-obstructive coronary arteries.

Methods: A total of 564 troponin-positive patients with non-obstructive coronary arteries at coronary angiography and available baseline creatinine levels were stratified according to baseline renal function (normal/stage 1: estimated glomerular filtration rate [eGFR] >90 ml/min/1.73m, stage 2: 60 to 89 ml/min/1.73m, stage 3: 30 to 59 ml/min/1.73m, and stage 4: <30 ml/min/1.73m). The primary outcome measure was mortality at a median follow-up was 100 [12-380] days.

Results: A total of 73 (12.9%), 195 (34.6%), 231 (41.0%), and 65 (11.5%) patients were in the normal/stage 1, stage 2, stage 3, and stage 4 renal dysfunction groups. With progressive renal impairment, patients were older, more frequently presented with established coronary or peripheral artery disease, and had an increased prevalence of cardiovascular risk factors. Cumulative mortality increased with progressive renal dysfunction (normal/stage 1: 0.0%, stage 2: 3.6%, stage 3: 12.1%, stage 4: 32.3%, log rank p < 0.001). A 10 ml/min/1.73m incremental decrease in eGFR was associated with an adjusted HR for mortality of 1.43 (95% CI 1.20-1.72, p < 0.001).

Conclusions: Renal impairment was associated with mortality in patients presenting with elevated cardiac troponin and non-obstructive coronary arteries. Hence, renal function should be incorporated into the risk stratification of these patients.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.046DOI Listing
February 2021

Impact of a nationwide COVID-19 lockdown on acute coronary syndrome referrals.

Cardiol J 2020 9;27(5):633-635. Epub 2020 Jul 9.

University Heart Center Zurich.

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http://dx.doi.org/10.5603/CJ.a2020.0091DOI Listing
November 2020

Diagnostic performance of angiography-based quantitative flow ratio for the identification of myocardial ischemia as assessed by N-ammonia myocardial perfusion imaging positron emission tomography.

Int J Cardiol 2020 09 28;314:13-19. Epub 2020 Apr 28.

Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland. Electronic address:

Background: Quantitative flow ratio (QFR) is a novel, adenosine-free method for functional lesion interrogation based on 3-dimensional quantitative coronary angiography and computational algorithms. We sought to investigate the diagnostic performance of QFR versus myocardial perfusion imaging positron emission tomography (MPI-PET), which yields the highest accuracy for detection of myocardial ischemia.

Methods: Diagnostic performance of QFR versus MPI-PET was assessed in consecutive patients undergoing both clinically indicated coronary angiography and N-ammonia MPI-PET within a six-month period.

Results: Out of 176 patients (439 coronary arteries), 19.3% were women. Percent area stenosis was 45 [32-58] %. Myocardial ischemia on N-ammonia MPI-PET was detected in 106 (24.1%) vessel territories and hemodynamic significance defined as contrast-flow vessel QFR ≤ 0.80 was observed in 83 (18.9%) vessels. Diagnostic accuracy, sensitivity, and specificity of contrast-flow vessel QFR for the prediction of myocardial ischemia on N-ammonia MPI-PET were 92.5 (95% CI 89.6-94.7) %, 73.6 (95% CI 64.1-81.7) %, and 98.5 (95% CI 96.5-99.5) %, respectively. The AUCs for contrast-flow vessel QFR, percent diameter stenosis, and percent area stenosis were 0.85 (95% CI 0.81-0.88, p < 0.001), 0.76 (95% CI 0.71-0.79, p < 0.001) and 0.75 (95% CI 0.70-0.79, p < 0.001), respectively.

Conclusions: QFR, a novel diagnostic tool for functional coronary lesion assessment, provides good diagnostic agreement with MPI-PET and superior diagnostic accuracy for the detection of myocardial ischemia as compared to anatomic indices. Future studies will have to determine the non-inferiority of QFR to fractional flow reserve with respect to clinical outcomes.
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http://dx.doi.org/10.1016/j.ijcard.2020.04.069DOI Listing
September 2020

Dysfunctional HDL and inflammation: a noxious liaison in adolescents with type 1 diabetes.

Eur Heart J 2019 11;40(43):3567-3570

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

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http://dx.doi.org/10.1093/eurheartj/ehz502DOI Listing
November 2019

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

Effect of Physical Disability on Mortality in Elderly Patients of ≥80 Years of Age Undergoing Percutaneous Coronary Intervention.

Am J Cardiol 2018 08 20;122(4):537-541. Epub 2018 Jun 20.

Department of Cardiology, Charité - University Medicine Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Berlin, Germany. Electronic address:

Functional decrease has been linked with adverse events in different clinical contexts. The predictive role of activity of daily living status as assessed by the Barthel index (BI) in elderly patients who underwent percutaneous coronary intervention (PCI) has not been investigated, yet. In this study, a total of 616 patients (≥80 years) who underwent PCI between January 2009 and December 2014 and with available activity of daily living data on admission were stratified according to BI (low BI <85, intermediate BI 85 to 95, high BI 100). The primary end point was all-cause mortality at a total follow-up of 442 days (interquartile range 47 to 1243). Of the 616 patients, 178 (29%), 128 (21%), and 310 (50%) were in the low, the intermediate, and the high BI groups, respectively. All-cause mortality was 10%, 13%, and 5% in the low, the intermediate, and the high BI groups, respectively (log-rank p <0.001). Belonging to the high BI group was associated with a reduced risk of all-cause mortality (hazard ratio 0.35, 95% confidence interval 0.18 to 0.69, p = 0.002), and associations remained significant after multivariable adjustments (adjusted hazard ratio 0.34, 95% confidence interval 0.13 to 0.93, p = 0.04). Functional capacity was identified as independent predictor of survival in a large cohort of patients who underwent PCI. In conclusion, activities of daily living should be incorporated into the risk stratification of elderly patients with coronary artery disease.
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http://dx.doi.org/10.1016/j.amjcard.2018.04.055DOI Listing
August 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

Catch miR if you can - Transcoronary gradients of HDL-bound microRNAs.

Int J Cardiol 2018 02;253:145-147

Department of Cardiology, Charité University Medicine Berlin, Campus Benjamin Franklin (CBF), Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2017.11.059DOI Listing
February 2018

Left atrial appendage angiography is associated with the incidence and number of magnetic resonance imaging-detected brain lesions after percutaneous catheter-based left atrial appendage closure.

Heart Rhythm 2018 01;15(1):3-8

Department of Cardiology, Charité-Universitätsmedizin Berlin, University Hospital, Berlin, Germany; Berlin Institute of Health, Berlin, Germany; Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK), Partner Site Berlin, Germany.

Background: Percutaneous catheter-based left atrial appendage closure (LAAC) is a procedure being increasingly performed in patients with atrial fibrillation and high bleeding risk.

Objective: The purpose of this study was to evaluate the incidence of magnetic resonance imaging (MRI)-detected acute brain lesions (ABLs) as well as potential changes in neurocognitive function after percutaneous LAAC in patients with atrial fibrillation.

Methods: Brain MRI at 3 T was performed within 24 hours before and after LAAC along with neurologic (National Institutes of Health Stroke Scale [NIHSS] score) and cognitive (Montreal Cognitive Assessment [MoCA] test) assessment. Acquired MRI sequences included high-resolution diffusion-weighted imaging as well as fluid-attenuated inversion recovery.

Results: Successful device implantation was achieved in all 23 patients (age 74.1 ± 10.5 years; 16 male) using the Amulet (n = 18), Occlutech (n = 3), or LAmbre (n = 2) device. Thirty-seven ABLs were detected by MRI in 12 of 23 patients (52%) after LAAC. The number of periprocedural LAA angiographies was significantly higher in patients with ABL than in those without ABL (1.67 ± 0.65 vs 1.18 ± 0.41; P = .048) and was associated with a higher number of ABL (ρ = 0.615; P = .033). Compared to pre-LAAC assessment, post-LAAC MoCA and NIHSS scores revealed similar results. After LAAC, MoCA test (mean 24.1 ± 4.6 vs 23.2 ± 4.6; P = .09) and NIHSS score (mean 1.0 ± 1.7 vs 1.2 ± 1.8; P = .1) were similar between patients with and those without ABL, respectively.

Conclusion: MRI-detected ABLs are commonly observed after percutaneous LAAC. The number of LAA angiographies is significantly associated with the number of ABLs; however, the clinical implications of ABL have yet to be determined.
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http://dx.doi.org/10.1016/j.hrthm.2017.11.015DOI Listing
January 2018

Impact of concomitant mitral regurgitation on transvalvular gradient and flow in severe aortic stenosis: a systematic ex vivo analysis of a subentity of low-flow low-gradient aortic stenosis.

EuroIntervention 2018 02;13(14):1635-1644

University Heart Center Jena, Jena, Germany.

Aims: Evaluation of aortic stenosis (AS) is based on echocardiographic measurement of mean pressure gradient (MPG), flow velocity (Vmax) and aortic valve area (AVA). The objective of the present study was to analyse the impact of systemic haemodynamic variables and concomitant mitral regurgitation (MR) on aortic MPG, Vmax and AVA in severe AS.

Methods And Results: A pulsatile circulatory model was designed to study function and interdependence of stenotic aortic (AVA: 1.0 cm², 0.8 cm² and 0.6 cm²) and insufficient mitral prosthetic valves (n=8; effective regurgitant orifice area [EROA] <0.2 cm² vs. >0.4 cm²) using Doppler ultrasound. In the absence of severe MR, a stepwise increase of stroke volume (SV) and a decrease of AVA was associated with a proportional increase of aortic MPG. When MR with EROA <0.2 cm² vs. >0.4 cm² was introduced, forward SV decreased significantly (70.9±1.1 ml vs. 60.8±1.6 ml vs. 47.4±1.1 ml; p=0.02) while MR volume increased proportionally. This was associated with a subsequent reduction of aortic MPG (57.1±9.4 mmHg vs. 48.6±13.8 mmHg vs. 33.64±9.5 mmHg; p=0.035) and Vmax (5.09±0.4 m/s vs. 4.91±0.73 m/s vs. 3.75±0.57 m/s; p=0.007). Calculated AVA remained unchanged (without MR: AVA=0.53±0.04 cm² vs. with MR: AVA=0.52±0.05 cm²; p=ns). In the setting of severe AS without MR, changes of vascular resistance (SVR) and compliance (C) did not impact on aortic MPG (low SVR and C: 66±13.8 mmHg and 61.1±20 mmHg vs. high SVR and C: 60.9±9.2 mmHg and 71.5±13.5 mmHg; p=ns) In concomitant severe MR, aortic MPG and Vmax were not significantly reduced by increased SVR (36.6±2.2 mmHg vs. 34.9±5.6 mmHg, p=0.608; 3.89±0.18 m/s vs. 3.96±0.28 m/s; p=ns).

Conclusions: Systemic haemodynamic variables and concomitant MR may potentially affect diagnostic accuracy of echocardiographic AS evaluation. As demonstrated in the present study, MPG and Vmax are flow-dependent and significantly reduced by a reduction of forward SV from concomitant severe MR, resulting in another entity of low-flow low-gradient aortic stenosis. In contrast, calculated AVA appears to be a robust parameter of AS evaluation if severe MR is present. Changes of SVR and C did not affect the diagnostic accuracy of AS evaluation.
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http://dx.doi.org/10.4244/EIJ-D-17-00476DOI Listing
February 2018

Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives.

Eur Heart J 2018 08;39(29):2704-2716

Department of Cardiology, CBF, CC11, Charite Universitätsmedizin Berlin, Campus Benjamin Franklin, Charite Centrum 11 (Cardiovascular Medicine), Hindenburgdamm 20, Berlin, Germany.

Recent research has demonstrated that the non-coding genome plays a key role in genetic programming and gene regulation during development as well as in health and cardiovascular disease. About 99% of the human genome do not encode proteins, but are transcriptionally active representing a broad spectrum of non-coding RNAs (ncRNAs) with important regulatory and structural functions. Non-coding RNAs have been identified as critical novel regulators of cardiovascular risk factors and cell functions and are thus important candidates to improve diagnostics and prognosis assessment. Beyond this, ncRNAs are rapidly emgerging as fundamentally novel therapeutics. On a first level, ncRNAs provide novel therapeutic targets some of which are entering assessment in clinical trials. On a second level, new therapeutic tools were developed from endogenous ncRNAs serving as blueprints. Particularly advanced is the development of RNA interference (RNAi) drugs which use recently discovered pathways of endogenous short interfering RNAs and are becoming versatile tools for efficient silencing of protein expression. Pioneering clinical studies include RNAi drugs targeting liver synthesis of PCSK9 resulting in highly significant lowering of LDL cholesterol or targeting liver transthyretin (TTR) synthesis for treatment of cardiac TTR amyloidosis. Further novel drugs mimicking actions of endogenous ncRNAs may arise from exploitation of molecular interactions not accessible to conventional pharmacology. We provide an update on recent developments and perspectives for diagnostic and therapeutic use of ncRNAs in cardiovascular diseases, including atherosclerosis/coronary disease, post-myocardial infarction remodelling, and heart failure.
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http://dx.doi.org/10.1093/eurheartj/ehx165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454570PMC
August 2018

Profiling and validation of circulating microRNAs for cardiovascular events in patients presenting with ST-segment elevation myocardial infarction.

Eur Heart J 2017 Feb;38(7):511-515

Department of Cardiology, Charité Berlin - University Medicine, Campus Benjamin Franklin and Berlin Institute of Health (BIH), Hindenburgdamm 30, 12203 Berlin, Germany.

Aims: MicroRNAs (miRNA) are important non-coding modulators controlling patterns of gene expression. However, profiling and validation of circulating miRNA levels related to adverse cardiovascular outcome has not been performed in patients with an acute coronary syndrome (ACS).

Methods And Results: In a multicentre, prospective ACS cohort, 1002 out of 2168 patients presented with ST-segment elevation myocardial infarction (STEMI). Sixty-three STEMI patients experienced an adjudicated major cardiovascular event (MACE, defined as cardiac death or recurrent myocardial infarction) within 1 year of follow-up. From a miRNA profiling in a matched derivation case-control cohort, 14 miRNAs were selected for validation. Comparing 63 cases vs. 126 controls, 3 miRNAs were significantly differentially abundant. In patients with MACE, miR-26b-5p levels (P = 0.038) were decreased, whereas miR-320a (P = 0.047) and miR-660-5p (P = 0.01) levels were increased. MiR-26b-5p has been suggested to prevent adverse cardiomyocyte hypertrophy, whereas miR-320a promotes cardiomyocyte death and apoptosis, and miR-660-5p has been related to active platelet production. This suggests that miR-26b-5p, miR-320a, and miR-660-5p may reflect alterations of different pathophysiological pathways involved in clinical outcome after ACS. Consistently, these three miRNAs reliably discriminated cases from controls [area under the receiver-operating characteristic curve (AUC) in age- and sex-adjusted Cox regression for miR-26b-5p = 0.707, miR-660-5p = 0.683, and miR-320a =0.672]. Combination of the three miRNAs further increased AUC to 0.718. Importantly, addition of the three miRNAs to both, the Global Registry of Acute Coronary Events (GRACE) score and a clinical model increased AUC from 0.679 to 0.720 and 0.722 to 0.732, respectively, with a net reclassification improvement of 0.20 in both cases.

Conclusion: This is the first study performing profiling and validation of miRNAs that are associated with adverse cardiovascular outcome in patients with STEMI. MiR-26b-5p, miR-320a, and miR-660-5p discriminated for MACE and increased risk prediction when added to the GRACE score and a clinical model. These findings suggest that the release of specific miRNAs into circulation may reflect the activation of molecular pathways that impact on clinical outcome after STEMI.
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http://dx.doi.org/10.1093/eurheartj/ehw563DOI Listing
February 2017

Lidocaine Enhances Contractile Function of Ischemic Myocardial Regions in Mouse Model of Sustained Myocardial Ischemia.

PLoS One 2016 3;11(5):e0154699. Epub 2016 May 3.

Cardioimmunology, Center of Molecular Cardiology, University of Zurich, Wagistr. 12, CH-8952, Schlieren, Switzerland.

Rationale: Perioperative myocardial ischemia is common in high-risk patients. The use of interventional revascularisation or even thrombolysis is limited in this patient subset due to exceedingly high bleeding risks. Blockade of voltage-gated sodium channels (VGSC) with lidocaine had been suggested to reduce infarct size and cardiomyocyte cell death in ischemia/reperfusion models. However, the impact of lidocaine on cardiac function during sustained ischemia still remains unclear.

Methods: Sustained myocardial ischemia was induced by ligation of the left anterior descending artery in 12-16 weeks old male BALB/c mice. Subcutaneous lidocaine (30 mg/kg) was used to block VGSC. Cardiac function was quantified at baseline and at 72h by conventional and speckle-tracking based echocardiography to allow high-sensitivity in vivo phenotyping. Infarct size and cardiomyocyte cell death were assessed post mortem histologically and indirectly using troponin measurements.

Results: Ischemia strongly impaired both, global systolic and diastolic function, which were partially rescued in lidocaine treated in mice. No differences regarding infarct size and cardiomyocyte cell death were observed. Mechanistically, and as shown with speckle-tracking analysis, lidocaine specifically improves residual contractility in the ischemic but not in the remote, non-ischemic myocardium.

Conclusion: VGSC blockade with lidocaine rescues function of ischemic myocardium as a potential bridging to revascularisation in the setting of perioperative myocardial ischemia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154699PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854463PMC
July 2017

Safety profile of prasugrel and clopidogrel in patients with acute coronary syndromes in Switzerland.

Heart 2015 Jun 20;101(11):854-63. Epub 2015 Mar 20.

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

Objective: To assess safety up to 1 year of follow-up associated with prasugrel and clopidogrel use in a prospective cohort of patients with acute coronary syndromes (ACS).

Methods: Between 2009 and 2012, 2286 patients invasively managed for ACS were enrolled in the multicentre Swiss ACS Bleeding Cohort, among whom 2148 patients received either prasugrel or clopidogrel according to current guidelines. Patients with ST-elevation myocardial infarction (STEMI) preferentially received prasugrel, while those with non-STEMI, a history of stroke or transient ischaemic attack, age ≥75 years, or weight <60 kg received clopidogrel or reduced dose of prasugrel to comply with the prasugrel label.

Results: After adjustment using propensity scores, the primary end point of clinically relevant bleeding events (defined as the composite of Bleeding Academic Research Consortium, BARC, type 3, 4 or 5 bleeding) at 1 year, occurred at a similar rate in both patient groups (prasugrel/clopidogrel: 3.8%/5.5%). Stratified analyses in subgroups including patients with STEMI yielded a similar safety profile. After adjusting for baseline variables, no relevant differences in major adverse cardiovascular and cerebrovascular events were observed at 1 year (prasugrel/clopidogrel: cardiac death 2.6%/4.2%, myocardial infarction 2.7%/3.8%, revascularisation 5.9%/6.7%, stroke 1.0%/1.6%). Of note, this study was not designed to compare efficacy between prasugrel and clopidogrel.

Conclusions: In this large prospective ACS cohort, patients treated with prasugrel according to current guidelines (ie, in patients without cerebrovascular disease, old age or underweight) had a similar safety profile compared with patients treated with clopidogrel.

Clinical Trial Registration Number: SPUM-ACS: NCT01000701; COMFORTABLE AMI: NCT00962416.
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http://dx.doi.org/10.1136/heartjnl-2014-306925DOI Listing
June 2015

Genetic deletion of the adaptor protein p66Shc increases susceptibility to short-term ischaemic myocardial injury via intracellular salvage pathways.

Eur Heart J 2015 Feb 21;36(8):516-26a. Epub 2014 Oct 21.

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland Department of Cardiology, University Heart Center, Center for Molecular Cardiology, University Hospital and University of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland

Aims: Several intracellular mediators have been implicated as new therapeutic targets against myocardial ischaemia and reperfusion injury. However, clinically effective salvage pathways remain undiscovered. Here, we focused on the potential role of the adaptor protein p66(Shc) as a regulator of myocardial injury in a mouse model of cardiac ischaemia and reperfusion.

Methods And Results: Adult male p66(Shc) deficient (p66(Shc) (-/-)) and C57Bl/6 wild-type (WT) mice were exposed to 30, 45, or 60 min of ischaemia and reperfusion (5, 15 min, or 24 h). Infarct size, systemic and intracardiac inflammation and oxidants, as well as cytosolic and mitochondrial apoptotic pathways were investigated. Following 30, but not 45 or 60 min of ischaemia, genetic p66(Shc) deficiency was associated with larger infarcts. In WT mice, in vivo p66(Shc) knock down by siRNA with transient protein deficiency confirmed these findings. P66(Shc) inhibition was not associated with any modification in post-infarction inflammation, oxidative burst nor cardiac vessel density or structure. However, in p66(Shc) (-/-) mice activation of the protective and anti-apoptotic Reperfusion Injury Salvage Kinases and Survivor Activating Factor Enhancement pathways were blunted and mitochondrial swelling and cellular apoptosis via the caspase-3 pathway increased compared with WT.

Conclusions: Genetic deletion of p66(Shc) increased susceptibility to myocardial injury in response to short-term ischaemia and reperfusion in mice. Still, additional studies are needed for assessing the role of this pathway in acute coronary syndrome patients.
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http://dx.doi.org/10.1093/eurheartj/ehu400DOI Listing
February 2015

Vitamin D deficiency in orthopaedic patients: a single center analysis.

Acta Orthop Belg 2013 Oct;79(5):587-91

Department of Orthopedic Surgery, Pius-Hospital, Oldenburg, Germany.

Vitamin D is essential to bone health and is a major regulator of calcium homeostasis. Many recent reports demonstrated worldwide high rates of vitamin D deficiency, but few studies have been published on the vitamin D status of orthopaedic patients. The present study aimed to investigate the extent of hypovitaminosis D of orthopaedic patients and possible variations in vitamin D status according to the body region which was scheduled to undergo surgery. We measured the vitamin D level of 1119 patients consecutively admitted to an orthopaedic surgery department of a university hospital in Germany in 2011. The prevalence of normal (< or =30 ng/ml), insufficient (20-30 ng/ml) and deficient (< or =20 ng/ml) 25-OH-D levels was determined. Serum Vitamin D levels and rates of insufficiency and deficiency were compared between the different cohorts using two-tailed tests. The level of significance was set at p < or =0.05. The serum 25-OH-D levels for all participants were normally distributed, with a mean of 2057 ng/ml. Overall, we noted an alarmingly high rate of vitamin D insufficiency or deficiency among orthopaedic patients. No significant difference was found related with the various body regions scheduled to undergo surgery. Given the well-known effects of vitamin D on bone metabolism and muscle health, vitamin D insufficiency may negatively affect patients.
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October 2013

PI3K/p110α inhibition selectively interferes with arterial thrombosis and neointima formation, but not re-endothelialization: potential implications for drug-eluting stent design.

Eur Heart J 2014 Mar 11;35(12):808-20. Epub 2013 Dec 11.

Cardiology, Cardiovascular Center, University Hospital Zürich, Rämistrasse 100, Zurich 8091, Switzerland.

Background: Impaired re-endothelialization and stent thrombosis are a safety concern associated with drug-eluting stents (DES). PI3K/p110α controls cellular wound healing pathways, thereby representing an emerging drug target to modulate vascular homoeostasis after injury.

Methods And Results: PI3K/p110α was inhibited by treatment with the small molecule inhibitor PIK75 or a specific siRNA. Arterial thrombosis, neointima formation, and re-endothelialization were studied in a murine carotid artery injury model. Proliferation and migration of human vascular smooth muscle cell (VSMC) and endothelial cell (EC) were assessed by cell number and Boyden chamber, respectively. Endothelial senescence was evaluated by the β-galactosidase assay, endothelial dysfunction by organ chambers for isometric tension. Arterial thrombus formation was delayed in mice treated with PIK75 when compared with controls. PIK75 impaired arterial expression and activity of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1); in contrast, plasma clotting and platelet aggregation did not differ. In VSMC and EC, PIK75 inhibited expression and activity of TF and PAI-1. These effects occurred at the transcriptional level via the RhoA signalling cascade and the transcription factor NFkB. Furthermore, inhibition of PI3K/p110α with PIK75 or a specific siRNA selectively impaired proliferation and migration of VSMC while sparing EC completely. Treatment with PIK75 did not induce endothelial senescence nor inhibit endothelium-dependent relaxations. In line with this observation, treatment with PIK75 selectively inhibited neointima formation without affecting re-endothelialization following vascular injury.

Conclusion: Following vascular injury, PI3K/p110α inhibition selectively interferes with arterial thrombosis and neointima formation, but not re-endothelialization. Hence, PI3K/p110α represents an attractive new target in DES design.
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http://dx.doi.org/10.1093/eurheartj/eht496DOI Listing
March 2014

Current status of cell-based therapy for heart failure.

Curr Heart Fail Rep 2013 Jun;10(2):165-76

Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland.

In the last two decades, morbidity and mortality of patients with chronic heart failure could be further reduced by improved pharmacological and cardiac device therapies. However, despite these advances, there is a substantial unmet need for novel therapies, ideally specifically addressing repair and regeneration of the damaged or lost myocardium and its vasculature, given the limited endogenous potential for renewal of cardiomyocytes in adults. In this respect, cardiac cell-based therapies have gained substantial attention and have entered clinical feasibility and safety studies a decade ago. Different cell-types have been used, including bone marrow-derived mononuclear cells, bone marrow-derived mesenchymal stem cells, mobilized CD34+ cells, and more recently cardiac-derived c-kit+ stem cells and cardiosphere-derived cells. Some of these studies have suggested a potential of cell-based therapies to reduce cardiac scar size and to improve cardiac function in patients with ischemic cardiomyopathy. While first clinical trials examining the impact of cardiac cell-based therapy on clinical outcome have now been initiated, improved understanding of underlying mechanisms of action of cell-based therapies may lead to strategies for optimization of the cardiac repair potential of the applied cells. In experimental studies, direct in vivo reprogramming of cardiac fibroblasts towards cardiomyocytes, and microRNA-based promotion of cardiomyocyte proliferation and cardiac repair have recently been reported that may represent novel therapeutic approaches for cardiac regeneration that would not need cell-administration but rather directly stimulate endogenous cardiac regeneration. This review will focus mainly on recently completed clinical trials (within the last 2 years) investigating cardiac cell-based therapies and the current status of experimental studies for cardiac cell-based repair and regeneration with a potential for later translation into clinical studies in the future.
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http://dx.doi.org/10.1007/s11897-013-0134-zDOI Listing
June 2013

AngiomiR-126 expression and secretion from circulating CD34(+) and CD14(+) PBMCs: role for proangiogenic effects and alterations in type 2 diabetics.

Blood 2013 Jan 8;121(1):226-36. Epub 2012 Nov 8.

Cardiovascular Centre, University Hospital Zurich and Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland.

Several peripheral blood mononuclear cell (PBMC)-derived cell populations can promote angiogenesis, and differences in CD34(+) or CD14(+) surface expression have been used to separate PBMC subpopulations in this respect. AngiomiRs, microRNAs regulating angiogenesis, are key regulators of angiogenic processes. The present study examines differential angiomiR expression/secretion from CD34(+)/CD14(+), CD34(+)/CD14(-), CD34(-)/CD14(+), and CD34(-)/CD14(-) PBMC subsets and their relevance for different proangiogenic properties. Notably, both circulating human CD34(+)/14(+) and CD34(+)/14(-) PBMC subsets and their supernatants exerted more potent proangiogenic effects compared with CD34(-) PBMC subsets. MiR-126 was identified as most differentially expressed angiomiR in CD34(+) compared with CD34(-) PBMC subsets, determined by miR-array and RT-PCR validation. Modulation of miR-126 by anti-miR-126 or miR-mimic-126 treatment resulted in significant loss or increase of proangiogenic effects of CD34(+) PBMCs. MiR-126 levels in supernatants of CD34(+) PBMC subsets were substantially higher compared with CD34(-) PBMC subsets. MiR-126 was secreted in microvesicles/exosomes, and inhibition of their release impaired CD34(+) PBMCs proangiogenic effects. Notably, high-glucose treatment or diabetes reduced miR-126 levels of CD34(+) PBMCs, associated with impaired proangiogenic properties that could be rescued by miR-mimic-126 treatment. The present findings provide a novel molecular mechanism underlying increased proangiogenic effects of CD34(+) PBMCs, that is, angiomiR-126 expression/secretion. Moreover, an alteration of angiomiR-126 expression in CD34(+) PBMCs in diabetes provides a novel pathway causing impaired proangiogenic effects.
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http://dx.doi.org/10.1182/blood-2012-01-407106DOI Listing
January 2013

Loss of angiomiR-126 and 130a in angiogenic early outgrowth cells from patients with chronic heart failure: role for impaired in vivo neovascularization and cardiac repair capacity.

Circulation 2012 Dec 7;126(25):2962-75. Epub 2012 Nov 7.

Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland.

Background: MicroRNAs are key regulators of angiogenic processes. Administration of angiogenic early outgrowth cells (EOCs) or CD34(+) cells has been suggested to improve cardiac function after ischemic injury, in particular by promoting neovascularization. The present study therefore examines regulation of angiomiRs, microRNAs involved in angiogenesis, in angiogenic EOCs and circulating CD34(+) cells from patients with chronic heart failure (CHF) and the role for their cardiac repair capacity.

Methods And Results: Angiogenic EOCs and CD34(+) cells were isolated from patients with CHF caused by ischemic cardiomyopathy (n=45) and healthy subjects (n=35). In flow cytometry analyses, angiogenic EOCs were largely myeloid and positive for alternatively activated M2 macrophage markers. In vivo cardiac neovascularization and functional repair capacity were examined after transplantation into nude mice with myocardial infarction. Cardiac transplantation of angiogenic EOCs from healthy subjects markedly increased neovascularization and improved cardiac function, whereas no such effect was observed after transplantation of angiogenic EOCs from patients with CHF. Real-time polymerase chain reaction analysis of 14 candidate angiomiRs, expressed in angiogenic EOCs, revealed a pronounced loss of angiomiR-126 and -130a in angiogenic EOCs from patients with CHF that was also observed in circulating CD34(+) cells. Anti-miR-126 transfection markedly impaired the capacity of angiogenic EOCs from healthy subjects to improve cardiac function. miR-126 mimic transfection increased the capacity of angiogenic EOCs from patients with CHF to improve cardiac neovascularization and function.

Conclusions: The present study reveals a loss of angiomiR-126 and -130a in angiogenic EOCs and circulating CD34(+) cells from patients with CHF. Reduced miR-126 expression was identified as a novel mechanism limiting their capacity to improve cardiac neovascularization and function that can be targeted by miR-126 mimic transfection.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.112.093906DOI Listing
December 2012

Role of microRNAs in stem/progenitor cells and cardiovascular repair.

Cardiovasc Res 2012 Mar 1;93(4):614-22. Epub 2011 Dec 1.

Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland.

MicroRNAs (miRNAs), small non-coding RNAs, play a critical role in differentiation and self-renewal of pluripotent stem cells, as well as in differentiation of cardiovascular lineage cells. Several miRNAs have been demonstrated to repress stemness factors such as Oct4, Nanog, Sox2 and Klf4 in embryonic stem cells, thereby promoting embryonic stem cell differentiation. Furthermore, targeting of different miRNAs promotes reprogramming towards induced pluripotent stem cells. MicroRNAs are critical for vascular smooth muscle cell differentiation and phenotype regulation, and miR-143 and miR-145 play a particularly important role in this respect. Notably, these miRNAs are down-regulated in several cardiovascular disease states, such as in atherosclerotic lesions and vascular neointima formation. MicroRNAs are critical regulators of endothelial cell differentiation and ischaemia-induced neovascularization. miR-126 is important for vascular integrity, endothelial cell proliferation and neovascularization. miR-1 and miR-133 are highly expressed in cardiomyocytes and their precursors and regulate cardiomyogenesis. In addition, miR-499 promotes differentiation of cardiomyocyte progenitor cells. Notably, miRNA expression is altered in cardiovascular disease states, and recent studies suggest that dysregulated miRNAs may limit cardiovascular repair responses. Dysregulation of miRNAs may lead to an altered function and differentiation of cardiovascular progenitor cells, which is also likely to represent a limitation of autologous cell-based treatment approaches in these patients. These findings suggest that targeting of specific miRNAs may represent an interesting novel opportunity to impact on endogenous cardiovascular repair responses, including effects on stem/progenitor cell differentiation and functions. This approach may also serve to optimize cell-based treatment approaches in patients with cardiovascular disease.
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http://dx.doi.org/10.1093/cvr/cvr311DOI Listing
March 2012