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2.  Steady-State Equilibrium Phase Inversion Recovery ON-resonant Water Suppression (IRON) Magnetic Resonance Angiography in Conjunction with Superparamagnetic Nanoparticles. A Robust Technique for Imaging within a Wide Range of Contrast Agent Dosages 
Objectives
To investigate the ability of inversion recovery ON-resonant water suppression (IRON) in conjunction with P904 (superparamagnetic nanoparticles which consisting of a maghemite core coated with a low-molecular-weight amino-alcohol derivative of glucose) to perform steady-state equilibrium phase magnetic resonance angiography (MRA) over a wide dose range.
Materials and Methods
Experiments were approved by the institutional animal care committee. Rabbits (n=12) were imaged at baseline and serially after the administration of 10 incremental dosages of 0.57–5.7 mgFe/Kg P904. Conventional T1-weighted and IRON MRA were obtained on a clinical 1.5-T scanner to image the thoracic and abdominal aorta, and peripheral vessels. Contrast-to-noise ratios (CNR) and vessel sharpness were quantified.
Results
Using IRON MRA, CNR and vessel sharpness progressively increased with incremental dosages of the contrast agent P904, exhibiting constantly higher contrast values than T1-weighted MRA over a very wide range of contrast agent doses (CNR of 18.8±5.6 for IRON versus 11.1±2.8 for T1-weighted MRA at 1.71 mgFe/kg, p=0.02 and 19.8±5.9 for IRON versus −0.8±1.4 for T1-weighted MRA at 3.99 mgFe/kg, p=0.0002). Similar results were obtained for vessel sharpness in peripheral vessels, (Vessel sharpness of 46.76±6.48% for IRON versus 33.20±3.53% for T1-weighted MRA at 1.71 mgFe/Kg, p=0.002, and of 48.66±5.50% for IRON versus 19.00±7.41% for T1-weighted MRA at 3.99 mgFe/Kg, p=0.003).
Conclusion
Our study suggests that quantitative CNR and vessel sharpness after the injection of P904 are consistently higher for IRON MRA when compared to conventional T1-weighted MRA. These findings apply for a wide range of contrast agent dosages.
doi:10.1002/jmri.24043
PMCID: PMC3657577  PMID: 23418107
3.  S100A1 is released from ischemic cardiomyocytes and signals myocardial damage via Toll-like receptor 4 
EMBO Molecular Medicine  2014;6(6):778-794.
Members of the S100 protein family have been reported to function as endogenous danger signals (alarmins) playing an active role in tissue inflammation and repair when released from necrotic cells. Here, we investigated the role of S100A1, the S100 isoform with highest abundance in cardiomyocytes, when released from damaged cardiomyocytes during myocardial infarction (MI). Patients with acute MI showed significantly increased S100A1 serum levels. Experimental MI in mice induced comparable S100A1 release. S100A1 internalization was observed in cardiac fibroblasts (CFs) adjacent to damaged cardiomyocytes. In vitro analyses revealed exclusive S100A1 endocytosis by CFs, followed by Toll-like receptor 4 (TLR4)-dependent activation of MAP kinases and NF-κB. CFs exposed to S100A1 assumed an immunomodulatory and anti-fibrotic phenotype characterized i.e. by enhanced intercellular adhesion molecule-1 (ICAM1) and decreased collagen levels. In mice, intracardiac S100A1 injection recapitulated these transcriptional changes. Moreover, antibody-mediated neutralization of S100A1 enlarged infarct size and worsened left ventricular functional performance post-MI. Our study demonstrates alarmin properties for S100A1 from necrotic cardiomyocytes. However, the potentially beneficial role of extracellular S100A1 in MI-related inflammation and repair warrants further investigation.
doi:10.15252/emmm.201303498
PMCID: PMC4203355  PMID: 24833748
alarmin; cardiac fibroblast; damage-associated molecular pattern (DAMP); S100A1; Toll-like receptors (TLRs)
4.  Early discharge using single cardiac troponin and copeptin testing in patients with suspected acute coronary syndrome (ACS): a randomized, controlled clinical process study 
European Heart Journal  2014;36(6):369-376.
Aims
This randomized controlled trial (RCT) evaluated whether a process with single combined testing of copeptin and troponin at admission in patients with low-to-intermediate risk and suspected acute coronary syndrome (ACS) does not lead to a higher proportion of major adverse cardiac events (MACE) than the current standard process (non-inferiority design).
Methods and results
A total of 902 patients were randomly assigned to either standard care or the copeptin group where patients with negative troponin and copeptin values at admission were eligible for discharge after final clinical assessment. The proportion of MACE (death, survived sudden cardiac death, acute myocardial infarction (AMI), re-hospitalization for ACS, acute unplanned percutaneous coronary intervention, coronary artery bypass grafting, or documented life threatening arrhythmias) was assessed after 30 days. Intention to treat analysis showed a MACE proportion of 5.17% [95% confidence intervals (CI) 3.30–7.65%; 23/445] in the standard group and 5.19% (95% CI 3.32–7.69%; 23/443) in the copeptin group. In the per protocol analysis, the MACE proportion was 5.34% (95% CI 3.38–7.97%) in the standard group, and 3.01% (95% CI 1.51–5.33%) in the copeptin group. These results were also corroborated by sensitivity analyses. In the copeptin group, discharged copeptin negative patients had an event rate of 0.6% (2/362).
Conclusion
After clinical work-up and single combined testing of troponin and copeptin to rule-out AMI, early discharge of low- to intermediate risk patients with suspected ACS seems to be safe and has the potential to shorten length of stay in the ED. However, our results need to be confirmed in larger clinical trials or registries, before a clinical directive can be propagated.
doi:10.1093/eurheartj/ehu178
PMCID: PMC4320319  PMID: 24786301
Copeptin; Acute coronary syndrome (ACS); Rule-out; Acute myocardial infarction (AMI); Randomized controlled trial (RCT)
5.  When Do We Really Need Coronary Calcium Scoring Prior to Contrast-Enhanced Coronary Computed Tomography Angiography? Analysis by Age, Gender and Coronary Risk Factors 
PLoS ONE  2014;9(4):e92396.
Aims
To investigate the value of coronary calcium scoring (CCS) as a filter scan prior to coronary computed tomography angiography (CCTA).
Methods and Results
Between February 2008 and April 2011, 732 consecutive patients underwent clinically indicated CCTA. During this ‘control phase’, CCS was performed in all patients. In patients with CCS≥800, CCTA was not performed. During a subsequent ‘CCTA phase’ (May 2011–May 2012) another 200 consecutive patients underwent CCTA, and CCS was performed only in patients with increased probability for severe calcification according to age, gender and atherogenic risk factors. In patients where CCS was not performed, calcium scoring was performed in contrast-enhanced CCTA images. Significant associations were noted between CCS and age (r = 0.30, p<0.001) and coronary risk factors (χ2 = 37.9; HR = 2.2; 95%CI = 1.7–2.9, p<0.001). Based on these associations, a ≤3% pre-test probability for CCS≥800 was observed for males <61 yrs. and females <79 yrs. According to these criteria, CCS was not performed in 106 of 200 (53%) patients during the ‘CCTA phase’, including 47 (42%) males and 59 (67%) females. This resulted in absolute radiation saving of ∼1 mSv in 75% of patients younger than 60 yrs. Of 106 patients where CCS was not performed, estimated calcium scoring was indeed <800 in 101 (95%) cases. Non-diagnostic image quality due to calcification was similar between the ‘control phase’ and the ‘CCTA’ group (0.25% versus 0.40%, p = NS).
Conclusion
The value of CCS as a filter for identification of a high calcium score is limited in younger patients with intermediate risk profile. Omitting CCS in such patients can contribute to further dose reduction with cardiac CT studies.
doi:10.1371/journal.pone.0092396
PMCID: PMC3979653  PMID: 24714677
12.  Diagnostic performance of rising, falling, or rising and falling kinetic changes of high-sensitivity cardiac troponin T in an unselected emergency department population 
Background:
Current ESC guidelines for the diagnosis of myocardial infarction consider a rise and/or fall of cardiac biomarkers. However, whether rising or falling patterns of high-sensitivity cardiac troponin T (hs-cTnT) improve the discrimination of ST-elevation myocardial infarction (non-STEMI) from non-acute coronary syndromes (ACS) has not been evaluated yet.
Methods:
We compared protocols of rising and falling absolute and relative hs-cTnT changes in an unselected emergency department population.
Results:
A total of 635 patients with unstable angina pectoris (UAP), non-STEMI, or acute symptoms and increased hs-cTnT (>99th percentile) were enrolled. Of these, 572 patients met the inclusion criteria of consistently rising patterns (n=254, 44.4%), consistently falling patterns (n=224, 39.2%), or falling patterns after an initial rise (n=94, 16.4%). Final diagnoses included 66 (11.5%) patients with UAP, 141 (24.7%) patients with non-STEMI, and 365 (63.8%) patients with hs-cTnT elevations not due to ACS. Rising values were found more frequently in patients with non-STEMI, as compared to non-ACS (OR 3.69, 95% CI 2.46–5.53; p<0.0001), and falling patterns were observed more frequently in patients with non-ACS conditions (OR 3.56, 95% CI 2.24–5.63; p<0.001). Addition of rising but not falling changes increased diagnostic performance of hs-cTnT concentrations at presentation: positive: AUC 0.680 (95% CI 0.618–0.742) vs. 0.861 (95% CI 0.822–0.900; p<0.0001), negative: AUC 0.678 (95% CI 0.545–0.812) vs. 0.741 (95% CI 0.635–0.847). A 20% criterion as proposed by ESC guidelines performed equally for positive and negative changes only when admission hs-cTnT values were considered: AUC 0.785 (95% CI 0.726–0.845) vs. AUC 0.763 (95% CI 0.681–0.845); p=ns.
Conclusions:
Detection of rising but not falling hs-cTnT values improves discrimination of non-STEMI from non-ACS in an unselected emergency department population.
doi:10.1177/2048872613498517
PMCID: PMC3821831  PMID: 24338290
Diagnostic performance; high-sensitivity troponin T; negative changes; non-STEMI; positive changes
13.  Adjustment of the GRACE score by growth differentiation factor 15 enables a more accurate appreciation of risk in non-ST-elevation acute coronary syndrome 
European Heart Journal  2011;33(9):1095-1104.
Aims
The aim of the study was to evaluate whether knowledge of the circulating concentration of growth differentiation factor 15 (GDF-15) adds predictive information to the Global Registry of Acute Coronary Events (GRACE) score, a validated scoring system for risk assessment in non-ST-elevation acute coronary syndrome (NSTE-ACS). We also evaluated whether GDF-15 adds predictive information to a model containing the GRACE score and N-terminal pro-B-type natriuretic peptide (NT-proBNP), a prognostic biomarker already in clinical use.
Methods and results
The GRACE score, GDF-15, and NT-proBNP levels were determined on admission in 1122 contemporary patients with NSTE-ACS. Six-month all-cause mortality or non-fatal myocardial infarction (MI) was the primary endpoint of the study. To obtain GDF-15- and NT-proBNP-adjusted 6-month estimated probabilities of death or non-fatal MI, statistical algorithms were developed in a derivation cohort (n = 754; n = 66 reached the primary endpoint) and applied to a validation cohort (n = 368; n = 33). Adjustment of the GRACE risk estimate by GDF-15 increased the area under the receiver-operating characteristic curve (AUC) from 0.79 to 0.85 (P < 0.001) in the validation cohort. Discrimination improvement was confirmed by an integrated discrimination improvement (IDI) of 0.055 (P = 0.005). A net 31% of the patients without events were reclassified into lower risk, and a net 27% of the patients with events were reclassified into higher risk, resulting in a total continuous net reclassification improvement [NRI(>0)] of 0.58 (P = 0.002). Addition of NT-proBNP to the GRACE score led to a similar improvement in discrimination and reclassification. Addition of GDF-15 to a model containing GRACE and NT-proBNP led to a further improvement in model performance [increase in AUC from 0.84 for GRACE plus NT-proBNP to 0.86 for GRACE plus NT-proBNP plus GDF-15, P = 0.010; IDI = 0.024, P = 0.063; NRI(>0) = 0.42, P = 0.022].
Conclusion
We show that a single measurement of GDF-15 on admission markedly enhances the predictive value of the GRACE score and provides moderate incremental information to a model including the GRACE score and NT-proBNP. Our study is the first to provide simple algorithms that can be used by the practicing clinician to more precisely estimate risk in individual patients based on the GRACE score and a single biomarker measurement on admission. The rigorous statistical approach taken in the present study may serve as a blueprint for future studies exploring the added value of biomarkers beyond clinical risk scores.
doi:10.1093/eurheartj/ehr444
PMCID: PMC3888120  PMID: 22199121
GDF-15; NT-proBNP; GRACE score; Acute coronary syndrome; Risk stratification
14.  High-sensitive Troponin T increase after exercise in patients with pulmonary arterial hypertension 
Background
The current study aimed to investigate the release of myocardial high-sensitive Troponin T (hsTnT) in patients with pulmonary arterial hypertension (PAH) in response to maximal physical exercise.
Methods
In 24 patients with PAH, symptom-limited cardiopulmonary exercise testing was performed. hsTnT was measured by the novel hsTnT assay with a lower limit of detection of 2 ng/L and a total imprecision of less than 10% at the 99th percentile value. hsTnT was related to NT-proBNP, WHO functional class and right ventricular (RV) function. Serial measurement was performed before and 30 min, 180 min, and 300 min after exercise. Healthy volunteers served as a control group.
Results
In 21 PAH patients, hsTnT levels were detectable before exercise with a close correlation between hsTnT and NT-proBNP. hsTnT was detectable in all PAH patients after exercise and significantly increased from 7.5 ng/L at baseline to 14.62 ng/L after 300 min, whereas levels of NT-proBNP remained constant with time.
Conclusions
Using the novel hsTnT assay, the current study provides first evidence that hsTnT levels increase in PAH patients after maximal physical exercise, while levels of other biomarkers remain constant after exercise testing. This might provide new insights into pathophysiology and individual risk assessment in patients with PAH.
doi:10.1186/1471-2466-13-28
PMCID: PMC3644246  PMID: 23628072
High-sensitive Troponin T; Pulmonary arterial hypertension; Cardiopulmonary exercise testing
15.  Cost-effectiveness of ticagrelor versus clopidogrel for the prevention of atherothrombotic events in adult patients with acute coronary syndrome in Germany 
The aim of this health economic analysis was to compare the cost-effectiveness of ticagrelor versus clopidogrel within the German health care system. A two-part decision model was adapted to compare treatment with ticagrelor or clopidogrel in a low-dose acetylsalicylic acid (ASA) cohort (≤150 mg) for all ACS patients and subtypes NSTEMI/IA and STEMI. A decision-tree approach was chosen for the first year after initial hospitalization based on trial observations from a subgroup of the PLATO study. Subsequent years were estimated by a Markov model. Following a macro-costing approach, costs were based on official tariffs and published literature. Extensive sensitivity analyses were performed to test the robustness of the model. One-year treatment with ticagrelor is associated with an estimated 0.1796 life-years gained (LYG) and gained 0.1570 quality-adjusted life-years (QALY), respectively, over the lifetime horizon. Overall average cost with ticagrelor is estimated to be EUR 11,815 vs. EUR 11,387 with generic clopidogrel over a lifetime horizon. The incremental cost-effectiveness ratio (ICER) was EUR 2,385 per LYG (EUR 2,728 per QALY). Comparing ticagrelor with Plavix® or the lowest priced generic clopidogrel, ICER ranges from dominant to EUR 3,118 per LYG (EUR 3,567 per QALY). These findings are robust under various additional sensitivity analyses. Hence, 12 months of ACS treatment using ticagrelor/ASA instead of clopidogrel/ASA may offer a cost-effective therapeutic option, even when the generic price for clopidogrel is employed.
Electronic supplementary material
The online version of this article (doi:10.1007/s00392-013-0552-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s00392-013-0552-7
PMCID: PMC4269206  PMID: 23474908
Cost-effectiveness; Ticagrelor; Acute coronary syndrome; Prevention; Long-term impact; Germany

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