Kai C Wollert

Hannover Medical School, Hanover, Lower Saxony, Germany

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Publications (148)1096.92 Total impact

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    ABSTRACT: Supplementary information available for this article at http://www.nature.com/ncomms/2014/141218/ncomms6863/suppinfo/ncomms6863_S1.html
    Nat Commun. 12/2014; 5.
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    ABSTRACT: Myocardial inflammation is an emerging target for novel therapies and thus for molecular imaging. Positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) has been employed, but requires an approach for suppression of cardiomyocyte uptake. We tested clinically viable strategies for their suitability in mouse models in order to optimize preclinical imaging protocols.
    European journal of nuclear medicine and molecular imaging 11/2014; · 5.11 Impact Factor
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    ABSTRACT: -The American Heart Association Cardiovascular Health score (CVH score) is inversely associated with cardiovascular disease (CVD) incidence but the mechanisms underlying this association warrant exploration.
    Circulation 10/2014; · 15.20 Impact Factor
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    ABSTRACT: Biomarkers of cardiovascular stress have been associated with incident cardiovascular outcomes. Their relations with measures of subclinical atherosclerosis, as assessed by carotid intima-media thickness, have not been well described.
    Clinical chemistry. 09/2014;
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    ABSTRACT: Maladaptive remodelling of the arterial wall after mechanical injury (e. g. angioplasty) is characterised by inflammation, neointima formation and media hypertrophy, resulting in narrowing of the affected artery. Moreover, mechanical injury of the arterial wall causes loss of the vessel protecting endothelial cell monolayer. Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), a major downstream target of p38 MAPK, regulates inflammation, cell migration and proliferation, essential processes for vascular remodelling and reendothelialisation. Therefore, we investigated the role of MK2 in remodelling and reendothelialisation after arterial injury in genetically modified mice in vivo. Hypercholesterolaemic low-density-lipoprotein-receptor-deficient mice (ldlr-/-) were subjected to wire injury of the common carotid artery. MK2-deficiency (ldlr-/-/mk2-/-) nearly completely prevented neointima formation, media hypertrophy, and lumen loss after injury. This was accompanied by reduced proliferation and migration of MK2-deficient smooth muscle cells. In addition, MK2-deficiency severely reduced monocyte adhesion to the arterial wall (day 3 after injury, intravital microscopy), which may be attributed to reduced expression of the chemokine ligands CCL2 and CCL5. In line, MK2-deficiency significantly reduced the content of monocytes, neutrophiles and lymphocytes of the arterial wall (day 7 after injury, flow cytometry). In conclusion, in a model of endothelial injury (electric injury), MK2-deficiency strongly increased proliferation of endothelial cells and improved reendothelialisation of the arterial wall after injury. Deficiency of MK2 prevents adverse remodelling and promotes endothelial healing of the arterial wall after injury, suggesting that MK2-inhibition is a very attractive intervention to prevent restenosis after percutaneous therapeutic angioplasty.
    Thrombosis and Haemostasis 08/2014; Ahead of Print. · 5.76 Impact Factor
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    ABSTRACT: ᅟ: Imaging of inflammation early after myocardial infarction (MI) is a promising approach to the guidance of novel molecular interventions that support endogenous healing processes. (18)F-FDG PET has been used, but may be complicated by physiological myocyte uptake. We evaluated the potential of two alternative imaging targets: lactoferrin binding by (68)Ga-citrate and somatostatin receptor binding by (68)Ga-DOTATATE.
    European journal of nuclear medicine and molecular imaging 08/2014; · 5.11 Impact Factor
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    ABSTRACT: Background No five-year long-term follow-up data is available regarding the prognostic value of GDF-15. Our aim is to evaluate the long-term prognostic value of admission growth-differentiation factor 15 (GDF-15) regarding death or myocardial infarction (MI) in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). Methods This is a subanalysis from the ICTUS (Invasive versus Conservative Treatment in Unstable coronary Syndromes) trial, including troponin positive NSTE-ACS patients. The main outcome for the current analysis was 5-year death or spontaneous MI. GDF-15 samples were available in 1151 patients. The prognostic value of GDF-15, categorized into < 1200 ng/L, 1200–1800 ng/L and > 1800 ng/L, was assessed in unadjusted and adjusted Cox regression models. Adjustments were made for identified univariable risk factors. The additional discriminative and reclassification value of GDF-15 beyond the independent risk factors was assessed by the category-free net reclassification improvement (1/2 NRI(> 0)) and the integrated discrimination improvement (IDI) Results Compared to GDF-15 < 1200 ng/L, a GDF-15 > 1800 ng/L was associated with an increased hazard ratio for death or spontaneous MI, mainly driven by mortality. GDF-15 levels were predictive after adjustments for other identified predictors. Additional discriminative value was shown with the IDI, not with the NRI. Conclusion In patients presenting with NSTE-ACS and elevated troponin T, GDF-15 provides prognostic information in addition to identified predictors for mortality and spontaneous MI and can be used to identify patients at high risk during long-term follow-up.
    International Journal of Cardiology 03/2014; 172(2):356–363. · 6.18 Impact Factor
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    ABSTRACT: We investigated whether circulating concentrations of soluble ST2, growth differentiation factor-15 (GDF-15), and high-sensitivity troponin I (hsTnI) are associated with incident atrial fibrillation (AF) and whether these biomarkers improve current risk prediction models including AF risk factors, B-type natriuretic peptide (BNP), and C-reactive protein (CRP). We studied the relation between soluble ST2, GDF-15, and hsTnI and development of AF in Framingham Heart Study participants without prevalent AF. We used Cox proportional hazard regression analysis to examine the relation of incident AF during a 10-year follow-up period with each biomarker. We adjusted for standard AF clinical risk factors, BNP, and CRP. The mean age of the 3,217 participants was 59 ± 10 years, and 54% were women. During a 10-year follow-up, 242 participants developed AF. In age- and sex-adjusted models, GDF-15 and hsTnI were associated with risk of incident AF; however, after including the AF risk factors and BNP and CRP, only hsTnI was significantly associated with AF (hazard ratio per 1 SD of loge hsTnI, 1.12, 95% CI 1.00-1.26, P = .045). The c statistic of the base model including AF risk factors, BNP, and CRP was 0.803 (95% CI 0.777-0.830) and did not improve by adding individual or all 3 biomarkers. None of the discrimination and reclassification statistics were significant compared with the base model. In a community-based cohort, circulating hsTnI concentrations were associated with incident AF. None of the novel biomarkers evaluated improved AF risk discrimination or reclassification beyond standard clinical AF risk factors and biomarkers.
    American heart journal 01/2014; 167(1):109-115.e2. · 4.65 Impact Factor
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    ABSTRACT: Thrombomodulin, via its lectin-like domain, exhibits anti-inflammatory properties partly by sequestering the pro-inflammatory cytokine, high-mobility group box 1 (HMGB1). Since myocardial damage after ischemia and reperfusion is mediated by inflammation we evaluated the cardioprotective effects of the lectin like domain of thrombomodulin. Using an in vivo mouse model of transient ischemia and in vitro models of cardiomyocyte hypoxia we assessed the ability of the lectin like domain to suppress HMGB1-mediated activation of the receptors RAGE, Toll-like receptor (TLR) 2 and 4.Methods and Results30 min myocardial ischemia was induced in isoflurane anesthetized mice followed by 24 hours of reperfusion in wildtype-mice (WT), in mice lacking the lectin-like domain (TM(LeD/LeD)-mice) and in WT with systemic overexpression of the lectin-like domain of thrombomodulin induced by hydrodynamic transfection. Infarct size, HMGB1-protein and apoptotic cells were significantly increased in TM(LeD/LeD)- as compared to wildtype-mice. Neonatal rat cardiomyocytes transfected with TLR2-, TLR4- and RAGE-siRNA were exposed to hypoxia (0.8 % O2) and reoxygenation (21% O2). HMGB1 augmented hypoxia-induced apoptosis in TLR2- but not in RAGE- or TLR4-suppressed cells. Administration of HMGB1- and TLR2-blocking antibodies in TM(LeD/LeD)-mice prior to myocardial ischemia diminished apoptosis. Therapeutic systemic gene therapy using the lectin-like domain reduced the infarct size and HMGB1-protein levels 24 hours after reperfusion. The lectin-like domain of thrombomodulin suppresses HMGB1-induced and TLR2-mediated myocardial reperfusion injury and apoptosis in vitro and in vivo.
    Cardiovascular Research 12/2013; · 5.81 Impact Factor
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    ABSTRACT: Takotsubo cardiomyopathy (TTC) remains a potentially life-threatening disease, which is clinically indistinguishable from acute myocardial infarction (MI). Today, no established biomarkers are available for the early diagnosis of TTC and differentiation from MI. MicroRNAs (miRNAs/miRs) emerge as promising sensitive and specific biomarkers for cardiovascular disease. Thus, we sought to identify circulating miRNAs suitable for diagnosis of acute TTC and for distinguishing TTC from acute MI. After miRNA profiling, eight miRNAs were selected for verification by real-time quantitative reverse transcription polymerase chain reaction in patients with TTC (n = 36), ST-segment elevation acute myocardial infarction (STEMI, n = 27), and healthy controls (n = 28). We quantitatively confirmed up-regulation of miR-16 and miR-26a in patients with TTC compared with healthy subjects (both, P < 0.001), and up-regulation of miR-16, miR-26a, and let-7f compared with STEMI patients (P < 0.0001, P < 0.05, and P < 0.05, respectively). Consistent with previous publications, cardiac specific miR-1 and miR-133a were up-regulated in STEMI patients compared with healthy controls (both, P < 0.0001). Moreover, miR-133a was substantially increased in patients with STEMI compared with TTC (P < 0.05). A unique signature comprising miR-1, miR-16, miR-26a, and miR-133a differentiated TTC from healthy subjects [area under the curve (AUC) 0.835, 95% CI 0.733-0.937, P < 0.0001] and from STEMI patients (AUC 0.881, 95% CI 0.793-0.968, P < 0.0001). This signature yielded a sensitivity of 74.19% and a specificity of 78.57% for TTC vs. healthy subjects, and a sensitivity of 96.77% and a specificity of 70.37% for TTC vs. STEMI patients. Additionally, we noticed a decrease of the endothelin-1 (ET-1)-regulating miRNA-125a-5p in parallel with a robust increase of ET-1 plasma levels in TTC compared with healthy subjects (P < 0.05). The present study for the first time describes a signature of four circulating miRNAs as a robust biomarker to distinguish TTC from STEMI patients. The significant up-regulation of these stress- and depression-related miRNAs suggests a close connection of TTC with neuropsychiatric disorders. Moreover, decreased levels of miRNA125a-5p as well as increased plasma levels of its target ET-1 are in line with the microvascular spasm hypothesis of the TTC pathomechanism.
    European Heart Journal 09/2013; · 14.72 Impact Factor
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    ABSTRACT: The objective of the present analysis was to systematically examine the effect of intracoronary bone marrow cell (BMC) therapy on left ventricular (LV) function after ST-segment elevation myocardial infarction in various subgroups of patients by performing a collaborative meta-analysis of randomized controlled trials. We identified all randomized controlled trials comparing intracoronary BMC infusion as treatment for ST-segment elevation myocardial infarction. We contacted the principal investigator for each participating trial to provide summary data with regard to different pre-specified subgroups [age, diabetes mellitus, time from symptoms to percutaneous coronary intervention, infarct-related artery, LV end-diastolic volume index (EDVI), LV ejection fraction (EF), infarct size, presence of microvascular obstruction, timing of cell infusion, and injected cell number] and three different endpoints [change in LVEF, LVEDVI, and LV end-systolic volume index (ESVI)].Data from 16 studies were combined including 1641 patients (984 cell therapy, 657 controls). The absolute improvement in LVEF was greater among BMC-treated patients compared with controls: [2.55% increase, 95% confidence interval (CI) 1.83-3.26, P < 0.001]. Cell therapy significantly reduced LVEDVI and LVESVI (-3.17 mL/m&sup2;, 95% CI: -4.86 to -1.47, P < 0.001; -2.60 mL/m&sup2;, 95% CI -3.84 to -1.35, P < 0.001, respectively). Treatment benefit in terms of LVEF improvement was more pronounced in younger patients (age <55, 3.38%, 95% CI: 2.36-4.39) compared with older patients (age ≥55 years, 1.77%, 95% CI: 0.80-2.74, P = 0.03). This heterogeneity in treatment effect was also observed with respect to the reduction in LVEDVI and LVESVI. Moreover, patients with baseline LVEF <40% derived more benefit from intracoronary BMC therapy. LVEF improvement was 5.30%, 95% CI: 4.27-6.33 in patients with LVEF <40% compared with 1.45%, 95% CI: 0.60 to 2.31 in LVEF ≥40%, P < 0.001. No clear interaction was observed between other subgroups and outcomes. Intracoronary BMC infusion is associated with improvement of LV function and remodelling in patients after ST-segment elevation myocardial infarction. Younger patients and patients with a more severely depressed LVEF at baseline derived most benefit from this adjunctive therapy.
    European Heart Journal 09/2013; · 14.72 Impact Factor
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    ABSTRACT: Fibroblast activation protein α (FAP) is a membrane glycoprotein with dipeptidyl-peptidase and collagenase activity and is expressed in cancer, arthritis, and atherosclerotic plaques. We hypothesized that FAP can be measured quantitatively in the circulation and provide prognostic information in acute coronary syndrome (ACS). We assessed the performance of a commercially available FAP ELISA and the pre-analytic characteristics of the marker. We determined FAP concentrations in EDTA plasma samples from 101 apparently healthy blood donors and 407 patients with ACS. Patients were followed for 12months regarding all-cause mortality and non-fatal myocardial infarction (MI). FAP was stable at room temperature (for 1day) and 4°C (3days) and resistant to 3 freeze/thaw cycles. Recovery of recombinant human FAP ranged from 78 to 103% and serial dilutions of spiked samples resulted in measurements within 91 to 120% of expected values. Patients with ACS had lower plasma FAP concentrations compared with blood donors [median (25th-75th percentiles): 84 (69-101)ng/mL vs. 108 (87-124)ng/mL, P<0.001]. Patients presenting with FAP concentrations in the first quartile had a 3.0-fold higher risk of death (95% confidence interval 1.4-6.2) compared with patients in the second to fourth quartiles (P=0.004). FAP concentration was not related to the risk of MI. Our study is the first to associate FAP with prognosis in ACS. The favorable pre-analytic characteristics of FAP will facilitate future studies of the marker in other disease settings associated with altered FAP expression.
    International journal of cardiology 08/2013; · 6.18 Impact Factor
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    ABSTRACT: Background The objective of the present analysis was to systematically examine the effect of intracoronary bone marrow cell (BMC) therapy on left ventricular function after ST-segment elevation myocardial infarction in various subgroups of patients by performing a collaborative meta-analysis of randomized controlled trials. Methods We identified all randomized controlled trials comparing intracoronary BMC infusion as treatment for ST-segment elevation myocardial infarction . We contacted the principal investigator for each participating trial to provide summary data with regard to different prespecified subgroups (age, diabetes mellitus, time from symptoms to percutaneous coronary intervention, infarct related artery, left ventricular (LV) end-diastolic volume index (EDVI), LV ejection fraction (EF), infarct size, presence of microvascular obstruction, timing of cell infusion, and injected cell number) and 3 different endpoints (change in LVEF, LVEDVI and LV end-systolic volume index (ESVI)). Results Data from 16 studies were combined including 1641 patients (984 cell therapy, 657 controls). The absolute improvement in LVEF was greater among BMC treated patients compared to controls: (2.55% increase, 95% Confidence Interval (CI) 1.83 to 3.26, p<0.001). Cell therapy significantly reduced LVEDVI and LVESVI (-3.17 mL/m², 95% CI -4.86 to -1.47, p<0.001; -2.60 mL/m², 95% CI 3.84 to -1.35, p<0.001, respectively). Treatment benefit in terms of LVEF improvement was more pronounced in younger patients (age <55, 3.38%, 95% CI 2.36 to 4.39) compared to older patients (age ≥55 years, 1.77%, 95% CI 0.80 to 2.74, p=0.03). This heterogeneity in treatment effect was also observed with respect to the reduction in LVEDVI and LVESVI. Moreover, patients with baseline LVEF<40% derived more benefit from intracoronary BMC therapy. LVEF improvement was 5.30%, 95% CI 4.27 to 6.33 in patients with LVEF <40% compared to 1.45%, 95% CI 0.60 to 2.31 in LVEF ≥40%, p<0.001. No clear interaction was observed between other subgroups and outcomes.
    European Heart Journal 08/2013; · 14.72 Impact Factor
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    Tibor Kempf, Kai C Wollert
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    ABSTRACT: Patients with adult respiratory distress syndrome (ARDS) are highly heterogeneous but current therapies are rather uniform and largely supportive. In the previous issue of Critical Care, Clark and colleagues report that the biomarker GDF-15 provides prognostic information in ARDS that is additive to that provided by the APACHE III score. Patients with high levels of growth-differentiation factor 15 (GDF-15) had a higher mortality and more complicated hospital course. Biomarkers such as GDF-15 may help us to identify patients at higher risk who may eventually benefit from more personalized and targeted therapies.
    Critical care (London, England) 07/2013; 17(4):173. · 4.72 Impact Factor
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    ABSTRACT: Growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) are emerging predictors of adverse clinical outcomes. We examined whether circulating concentrations are related to the development of kidney disease in the community.METHODS: Plasma GDF-15, sST2, and hsTnI concentrations were measured in 2614 Framingham Offspring cohort participants (mean age 57 years, 54% women) at the sixth examination cycle (1995-1998). Associations of biomarkers with incident chronic kidney disease [CKD, eGFR <60 mL · min(-1) · (1.73 m(2)) (-1), n = 276], microalbuminuria (urinary albumin to creatinine ratio ≥25 mg/g in women and 17 mg/g in men, n = 191), and rapid decline in renal function [decline in eGFR ≥3 mL · min(-1) · (1.73 m(2)) (-1) per year, n = 237], were evaluated using multivariable logistic regression; P < 0.006 was considered statistically significant in primary analyses.RESULTS: Participants were followed over a mean of 9.5 years. Higher plasma GDF-15 was associated with incident CKD (multivariable-adjusted OR 1.9 per 1-U increase in log-GDF-15, 95% CI 1.6-2.3, P < 0.0001) and rapid decline in renal function (odds ratio, 1.6; 95% CI, 1.3-1.8; P < 0.0001). GDF-15, sST2, and hsTnI had suggestive associations with incident microalbuminuria but did not meet the prespecified P-value threshold after multivariable adjustment. Adding plasma GDF-15 to clinical covariates improved risk prediction of incident CKD: the c-statistic increased from 0.826 to 0.845 (P = 0.0007), and categorical net reclassification was 6.3% (95% CI, 2.7-9.9%).CONCLUSIONS: Higher circulating GDF-15 is associated with incident renal outcomes and improves risk prediction of incident CKD. These findings may provide insights into the mechanisms of renal injury.
    Clinical Chemistry 07/2013; · 7.15 Impact Factor
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    ABSTRACT: Guidelines recommend the use of validated risk scores and a high-sensitivity cardiac troponin assay for risk assessment in non-ST-elevation acute coronary syndrome (NSTE-ACS). The incremental prognostic value of biomarkers in this context is unknown.METHODS: We calculated the Global Registry of Acute Coronary Events (GRACE) score and measured the circulating concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and 8 selected cardiac biomarkers on admission in 1146 patients with NSTE-ACS. We used an hs-cTnT threshold at the 99th percentile of a reference population to define increased cardiac marker in the score. The magnitude of the increase in model performance when individual biomarkers were added to GRACE was assessed by the change (Δ) in the area under the receiver-operating characteristic curve (AUC), integrated discrimination improvement (IDI), and category-free net reclassification improvement [NRI(>0)].RESULTS: Seventy-eight patients reached the combined end point of 6-month all-cause mortality or nonfatal myocardial infarction. The GRACE score alone had an AUC of 0.749. All biomarkers were associated with the risk of the combined end point and offered statistically significant improvement in model performance when added to GRACE (likelihood ratio test P ≤ 0.015). Growth differentiation factor 15 [ΔAUC 0.039, IDI 0.049, NRI(>0) 0.554] and N-terminal pro-B-type natriuretic peptide [ΔAUC 0.024, IDI 0.027, NRI(>0) 0.438] emerged as the 2 most promising biomarkers. Improvements in model performance upon addition of a second biomarker were small in magnitude.CONCLUSIONS: Biomarkers can add prognostic information to the GRACE score even in the current era of high-sensitivity cardiac troponin assays. The incremental information offered by individual biomarkers varies considerably, however.
    Clinical Chemistry 07/2013; · 7.15 Impact Factor
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    ABSTRACT: Cell- and molecule-based therapeutic strategies to support wound healing and regeneration after myocardial infarction (MI) are under development. These emerging therapies aim at sustained preservation of ventricular function by enhancing tissue repair after myocardial ischaemia and reperfusion. Such therapies will benefit from guidance with regard to timing, regional targeting, suitable candidate selection, and effectiveness monitoring. Such guidance is effectively obtained by non-invasive tomographic imaging. Infarct size, tissue characteristics, muscle mass, and chamber geometry can be determined by magnetic resonance imaging and computed tomography. Radionuclide imaging can be used for the tracking of therapeutic agents and for the interrogation of molecular mechanisms such as inflammation, angiogenesis, and extracellular matrix activation. This review article portrays the hypothesis that an integrated approach with an early implementation of structural and molecular tomographic imaging in the development of novel therapies will provide a framework for achieving the goal of improved tissue repair after MI.
    European heart journal cardiovascular Imaging. 05/2013;
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    ABSTRACT: Inhibition of hepcidin expression by erythropoietic signals is of great physiological importance, however the inhibitory pathways remain poorly understood. To investigate i) the direct effect of erythropoietin (Epo) and ii) the contribution of putative mediators on hepcidin repression, healthy volunteers were injected with a single dose of Epo, either low (63 IU/kg, n=8) or high (400 IU/kg, n=6). Low-dose Epo provoked hepcidin down-modulation within 24 hours; the effect was not immediate since hepcidin circadian variations were still present following injection. High-dose Epo induced no additional effect on the hepcidin response, i.e. hepcidin diurnal fluctuations were not abolished in spite of extremely high Epo levels. We did not find significant changes in putative mediators of hepcidin repression, such as transferrin saturation, soluble transferrin receptor, or growth differentiation factor 15. Furthermore, the potential hepcidin inhibitor, soluble hemojuvelin, was found unaltered by Epo stimulation. This finding was consistent with the absence of signs of iron deficiency observed at the level of skeletal muscle tissue. Our data suggest that hepcidin repression by erythropoietic signals in humans may not be controlled directly by Epo but mediated by a still undefined factor. This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 04/2013; · 2.55 Impact Factor
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    ABSTRACT: BACKGROUND: Growth differentiation factor 15 (GDF-15) is emerging as a powerful risk indicator in both cardiovascular disease patients and community-dwelling individuals. We investigated GDF-15 concentrations and their changes over 5 years in elderly individuals from the community, together with the underlying conditions and prognostic implications of these measurements.METHODS: We analyzed GDF-15 concentrations using a sandwich immunoassay in participants from the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study. Measurements were performed at both 70 (n = 1004) and 75 (n = 813) years of age. Median follow-up was 8.0 years.RESULTS: Over time, GDF-15 concentrations increased by 11.0% (P < 0.001). These changes were related to male sex, hypertension, diabetes, heart failure, renal function, and concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Significant relationships also emerged between changes in GDF-15 and NT-proBNP, C-reactive protein, and renal function between ages 70 and 75. The R(2) value of this model was 0.20. GDF-15 concentrations independently predicted all-cause mortality [hazard ratio 4.0 (95% CI 2.7-6.0)] with results obtained at ages 70 and 75 as updated covariates. Baseline GDF-15 concentrations improved prognostic discrimination and reclassification [c-statistic 0.06 (P = 0.006); integrated discrimination improvement = 0.030 (P = 0.004); category-free net reclassification improvement = 0.281 (P = 0.006)]. Change in GDF-15 concentrations over time independently predicted even all-cause mortality occurring after age 75 [hazard ratio 3.6 (95% CI 2.2-6.0)].CONCLUSIONS: GDF-15 concentrations and their changes over time are powerful predictors of mortality in elderly community-dwelling individuals. GDF-15 concentrations increase with aging, and these changes are explained only partially by cardiovascular risk factors, indicators of neurohumoral activation and inflammation, and renal function. Thus GDF-15 reflects both cardiovascular and other biological processes closely related to longevity.
    Clinical Chemistry 03/2013; · 7.15 Impact Factor
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    ABSTRACT: Myostatin is a muscle derived factor that functions as a negative regulator of skeletal muscle growth. Induction of myostatin expression was observed in rodent models of muscle wasting and in cachectic patients with cancer or pulmonary disease. Therefore, there is an increasing interest to use serum myostatin as a biomarker. We established an immunoradiometric sandwich assay (IRMA), which uses a commercially available chicken polyclonal, affinity purified antibody directed against human myostatin prodomain. We determined the serum concentrations of myostatin prodomain in 249 healthy individuals as well as 169 patients with heart failure, 53 patients with cancer and 44 patients with chronic pulmonary disease. The IRMA had a detection limit of 0.7ng/ml, an intraassay imprecision of ≤14.1% and an interassay imprecision of ≤ 18.9%. The specificity of our assay was demonstrated by size exclusion chromatography, detection of myostatin by Western-blotting and a SMAD-dependent transcriptional-reporter assay in the signal-rich serum fractions, as well as lack of interference by unspecific substances like albumin, hemoglobin or lipids. Myostatin prodomain was stable at room temperature and resistant to freeze-thaw cycles. Apparently healthy individuals over the age of 55 had a median myostatin prodomain serum concentration of 3.9ng/ml (25(th)-75(th) percentiles, 2-7ng/ml) and we could not detect increased levels in patients with stable chronic heart failure or cancer related weight loss. In contrast, we found strongly elevated concentrations of myostatin prodomain (median 26.9ng/ml, 25(th)-75(th) percentiles, 7-100ng/ml) in the serum of underweight patients with chronic pulmonary disease. We established a highly specific IRMA for the quantification of myostatin prodomain concentration in human serum. Our assay could be useful to study myostatin as a biomarker for example in patients with chronic pulmonary disease, as we detected highly elevated myostatin prodomain serum levels in underweight individuals of this group.
    PLoS ONE 01/2013; 8(11):e80454. · 3.53 Impact Factor

Publication Stats

6k Citations
1,096.92 Total Impact Points

Institutions

  • 1997–2014
    • Hannover Medical School
      • • Department of Cardiology and Angiology
      • • Department of Nuclear Medicine
      Hanover, Lower Saxony, Germany
  • 2010
    • University of Minnesota Twin Cities
      Minneapolis, Minnesota, United States
    • Brigham and Women's Hospital
      • TIMI Study Group
      Boston, MA, United States
  • 2009–2010
    • Uppsala University
      • • Department of Medical Sciences
      • • Department of Medical Biochemistry and Microbiology
      Uppsala, Uppsala, Sweden
  • 2008
    • Uppsala University Hospital
      Uppsala, Uppsala, Sweden
    • Universitätsmedizin Göttingen
      • Department of Cardiology and Pneumology
      Göttingen, Lower Saxony, Germany
  • 2000
    • The Institute for Molecular Medicine
      Huntington Beach, California, United States
  • 1994–1997
    • University of Freiburg
      • Department of Internal Medicine
      Freiburg, Baden-Württemberg, Germany
  • 1996
    • University of California, San Diego
      • Department of Medicine
      San Diego, CA, United States