[Show abstract][Hide abstract] ABSTRACT: Background: While area detector computed tomography (ADCT) is a useful tool for coronary artery disease (CAD) evaluation, myocardial perfusion imaging (MPI) with single photon emission computed tomography is a well-established method of predicting functional relevance of CAD. Purpose: We assess the usefulness for decision making using both ADCT and MPI and discussed from the standpoint of cost for diagnostic work-up and contrast agent. Method: Between January, 2013 to September, 2014, 78 patients underwent both ADCT and MPI within two months were analyzed their therapeutic strategy. From ADCT, severity of stenosis was divided non-significant(less than 50%), moderate (over or equal to 50% and less than 75%) and severe (over or equal to 75%). Summed difference score of MPI was judged as ischemia positive.
Result: Table showed the result and executed treatment strategy. Patients with significant stenosis by ADCT were 40 patients (51.3%) and patients with ischemia positive were 25 patients (33.8%). Invasive revasculization was performed higher (82.3%, p<0.01) for the patients with significant stenosis and ischemia than moderate stenosis with ischemia (25%) or significant stenosis without ischemia (39.1%). Before taking invasive therapy, examination with ADCT and MPI saved 63700 yen and about 100ml of contrast agent in each case based study as it was compared with the case with ADCT and coronary angiography without MPI in spite of slightly higher radiation dose (4mSv). Conclusion: The combined use of ADCT and MPI could choose effectively treatment strategy of CAD with a reduction of cost and contrast agent.
European heart journal cardiovascular Imaging; 05/2015
[Show abstract][Hide abstract] ABSTRACT: Purpose: The outcome of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) has improved by computed tomography (CT) or magnetic resonance (MR) for the characterization of left atrium (LA) anatomy before the procedure. However, no comparative data between CT and MR have been described regarding to the impact of different imaging modality. The aim of this study is to compare the procedural characteristics, overall radiation exposure and clinical outcomes between RFCA guided by image integration with CCT versus CMR.
Methods: Four hundred consecutive patients with drug-refractory paroxysmal or persistent AF were randomized to CT (Group 1; N: 200; mean age 61.6±10.9 yo; male:155) or MR (Group 2; N: 200; mean age 59.7±10.4 yo; male:166) for evaluation of LA before RFCA. CT was performed with 64-slices scanner and MR was performed with 1.5-T scanner using a non-triggered contrast enhancement magnetic resonance angiography sequence. All patients were subsequently treated by image integration-supported RFCA. Left atrium diameter, left atrium volume, variant of pulmonary veins anatomy, pulmonary veins ostial dimensions, procedural characteristics, overall radiation exposure and rate of AF recurrence were measured and compared between the two groups.
Results: The two groups were homogeneous in terms of demographic characteristics, cardiovascular risk factors, prevalence of persistent AF, medical therapy and echocardiographic characteristics. The mean follow-up was similar (557±302 vs. 523±265 days, respectively, p:0.24). Group 1 showed higher LA volume versus group 2 (117±46 vs. 101±40 mL, p<0.001). The procedural characteristics [fluoroscopy time (32.6±16.0 vs. 35.0±16.6 min, p:0.15); procedural duration (180.2±59.0 vs. 182.8±53.5, p:0.65, pulmonary veins identified (4±0.1 vs. 3.9±0.2, p:0.08); pulmonary veins targeted (3.9±0.4 vs. 3.9±0.4, p: 053); pulmonary veins isolated (3.9±0.4 vs. 3.9±0.4, p:0.9)] and the rate of AF recurrence (29% vs. 26%, p:0.5) were similar between the two groups. Group 1 showed a higher overall cumulative radiation exposure (40.4±23.7 vs. 32.8±23.5, p<0.005). and LA volume measured by MR was the most robust independent predictor of AF recurrence at multivariate analysis [(HR: 1.08 (1.01–1.15), p:0.02]
Conclusions: CT and MR appear to provide similar information before RFCA. However, MR integration- supported RFCA procedure seems to be associated with a lower overall cumulative radiation despite similar outcome in comparison with CT-guided RFCA.
[Show abstract][Hide abstract] ABSTRACT: Background:
Up to 50% of the patients still die or have to be rehospitalized during the first year after transcatheter aortic valve replacement (TAVR). This emphasizes the need for more strategic patient selection. The aim of this prospective observational cohort study was to compare the prognostic value of risk scores and circulating biomarkers to predict all-cause mortality and rehospitalization in patients undergoing TAVR.
We calculated the hazard ratios and C-statistics (area under the curve [AUC]) of 4 risk scores (logistic European System for Cardiac Operative Risk Evaluation [EuroSCORE], EuroSCORE II, Society of Thoracic Surgeons predicted risk of mortality, and German aortic valve score) and 5 biomarkers of inflammation and/or myocardial dysfunction (high-sensitivity C-reactive protein, growth differentiation factor (GDF)-15, interleukin-6, interleukin-8, and N-terminal pro-B-type natriuretic peptide) for the risk of death (n = 80) and the combination of death or rehospitalization (n = 132) during the first year after TAVR in 310 consecutive TAVR patients.
The EuroSCORE II and GDF-15 had the strongest predictive value for 1-year mortality (EuroSCORE II, AUC 0.711; GDF-15, AUC 0.686) and for the composite end point (EuroSCORE II, AUC 0.690; GDF-15, AUC 0.682). When added to the logistic EuroSCORE and EuroSCORE II, GDF-15 enhanced the prognostic performance of the score and enabled substantial reclassification of patients. Combinations of increasing tertiles of the logistic EuroSCORE or EuroSCORE II and GDF-15 allowed the stratification of the patients into subgroups with mortality rates ranging from 4.0% to 49.1% and death/rehospitalization rates ranging from 15.3% to 68.4%.
Our study identified GDF-15 in addition to the logistic EuroSCORE and the EuroSCORE II as the most promising predictors of a poor outcome after TAVR.
Journal of the American College of Cardiology 03/2015; 65(10):A1717. DOI:10.1016/S0735-1097(15)61717-X · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Manic depression is searching my soul, I know what I want, but I just don’t know, honey, how to go about getting it. Jimi Hendrix Infusion of autologous bone marrow mononuclear cells (BMMCs) into the infarct-related coronary artery has been shown in clinical trials to improve systolic function in patients with a large ST-segment elevation myocardial infarction (STEMI).1 Based on these results, it was hoped that BMMC infusions may represent a new strategy to protect this vulnerable patient population that continues to be at high risk of developing chronic heart failure. Trial results have been rather heterogeneous, however, and the latest clinical trials—timing in myocardial infarction evaluation (TIME) and SWiss Multicenter Intracoronary Stem Cells Study in Acute Myocardial Infarction (SWISS-AMI)—did not confirm a significant impact of BMMCs on LVEF after STEMI.S1 S2 To make matters worse, a hotly debated meta-analysis by Francis and colleagues has cast doubt on the scientific integrity of the available trial evidence. This study examined reports (abstracts and final publications) of all available BMMC trials for discrepancies in design, methods or results and reported a positive correlation between the number of discrepancies and the magnitude of LVEF improvement.S3 Given these recent developments, it has been argued that the clinical validation process of BMMC therapy may approach a dead end,S4 and that physicians need to reconsider whether BMMC therapies should be pursued at all.S5 It seems, the field has fallen into a state of depression and it is uncertain whether it will ever recover. Contrast this with the stem cell mania at the turn of the century, when a report that bone marrow-derived stem cells can generate de novo myocardium,S6 a claim that has been refuted since,S7 S8 electrified cardiologists around the globe (including this editorialist) and stimulated the first … [Full text of this article]
[Show abstract][Hide abstract] ABSTRACT: Paracrine-acting proteins are emerging as a central mechanism by which bone marrow cell-based therapies improve tissue repair and heart function after myocardial infarction (MI). We carried out a bioinformatic secretome analysis in bone marrow cells from patients with acute MI to identify novel secreted proteins with therapeutic potential. Functional screens revealed a secreted protein encoded by an open reading frame on chromosome 19 (C19orf10) that promotes cardiac myocyte survival and angiogenesis. We show that bone marrow-derived monocytes and macrophages produce this protein endogenously to protect and repair the heart after MI, and we named it myeloid-derived growth factor (MYDGF). Whereas Mydgf-deficient mice develop larger infarct scars and more severe contractile dysfunction compared to wild-type mice, treatment with recombinant Mydgf reduces scar size and contractile dysfunction after MI. This study is the first to assign a biological function to MYDGF, and it may serve as a prototypical example for the development of protein-based therapies for ischemic tissue repair.
Nature Medicine 01/2015; 21(2). DOI:10.1038/nm.3778 · 27.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Coronary heart disease is one of the main causes of death in the developed world, and treatment success remains modest, with high mortality rates within 1 year after myocardial infarction (MI). Thus, new therapeutic targets and effective treatments are necessary. Short telomeres are risk factors for age-associated diseases, including heart disease. Here we address the potential of telomerase (Tert) activation in prevention of heart failure after MI in adult mice. We use adeno-associated viruses for cardiac-specific Tert expression. We find that upon MI, hearts expressing Tert show attenuated cardiac dilation, improved ventricular function and smaller infarct scars concomitant with increased mouse survival by 17% compared with controls. Furthermore, Tert treatment results in elongated telomeres, increased numbers of Ki67 and pH3-positive cardiomyocytes and a gene expression switch towards a regeneration signature of neonatal mice. Our work suggests telomerase activation could be a therapeutic strategy to prevent heart failure after MI.
[Show abstract][Hide abstract] ABSTRACT: Purpose
Myocardial inflammation is an emerging target for novel therapies and thus for molecular imaging. Positron emission tomography (PET) with 18F-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.
C57BL/6 mice (n = 56) underwent FDG PET under various conditions. In healthy animals, the effect of low-dose (5 units/kg) or high-dose (500 units/kg, 15 min prior) intravenous heparin, extended fasting (18 h) and the impact of conscious injection with limited, late application of isoflurane anaesthesia after 40 min of conscious uptake were examined in comparison to ketamine/xylazine anaesthesia. Conscious injection/uptake strategies were further evaluated at 3 days after permanent coronary artery occlusion.
Under continuous isoflurane anaesthesia, neither heparin administration nor extended fasting significantly impacted myocardial 18F-FDG accumulation. Injection with 40 min uptake in awake mice resulted in a marked reduction of global myocardial 18F-FDG uptake compared to standard isoflurane anaesthesia (5.7 ± 1.1 %ID/g vs 30.2 ± 7.9 %ID/g, p
European journal of nuclear medicine and molecular imaging 11/2014; 42(5). DOI:10.1007/s00259-014-2956-7 · 5.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
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.
Methods and results:
We related the CVH score to circulating biomarkers and prevalent subclinical CVD (defined as ≥1 of the following: increased carotid intima-media thickness or stenosis, left ventricular hypertrophy [by ECG or echocardiography], left ventricular systolic dysfunction, microalbuminuria, and a reduced ankle-brachial index) in 2680 Framingham Study participants (mean age, 58 years; 55% women). After adjustment for age and sex, an ideal CVH score (nonsmoking status, ideal body mass index, regular physical activity, healthy diet, and an optimal profile of serum cholesterol, blood pressure, and glucose; 1 point for each) was associated with higher circulating concentrations of natriuretic peptides (N-terminal pro-atrial natriuretic peptide and B-type natriuretic peptide) and lower blood concentrations of plasminogen activator inhibitor-1, aldosterone, C-reactive protein, D-dimer, fibrinogen, homocysteine, and growth differentiation factor-15 levels (P<0.001 for all), as well as lower odds of subclinical disease (odds ratio, 0.74 per 1-unit increase in CVH score; 95% confidence interval, 0.68-0.80). The incidence of CVD (267 events over 16 years) was inversely associated with the CVH score in age- and sex-adjusted models (hazard ratio, 0.77 per 1-unit increase in CVH score; 95% confidence interval, 0.70-0.86), which was slightly attenuated upon adjustment for biomarkers and subclinical disease (hazard ratio, 0.87; 95% confidence interval, 0.78-0.97).
In our prospective community-based study, the inverse association between an ideal cardiovascular health score and CVD incidence was partly attributable to its favorable impact on CVD biomarker levels and subclinical disease.
[Show abstract][Hide abstract] ABSTRACT: Background:
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.
We measured plasma growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) in 3111 Framingham Offspring participants who also underwent carotid ultrasonography during the sixth examination (1995-1998, mean age 58 years, 54% women). Carotid measurements included maximal internal carotid artery (ICA) intima-media thickness (IMT), plaque presence (defined as ICA IMT >1.5 mm), and mean common carotid artery IMT. We carried out multivariable regressions for carotid measurements vs biomarkers using linear and logistic models; P < 0.0056 was deemed statistically significant.
Maximal ICA IMT was significantly associated with plasma GDF-15 [β-estimate 0.04 per 1-U increase in log(GDF-15), SE 0.01, P < 0.0001]. Similarly, the odds of having carotid plaque increased 33% [odds ratio 1.33 per 1-U increase in log(GDF-15), 95% CI 1.20-1.48, P < 0.0001]. In contrast, there was no significant association of maximal ICA IMT or plaque presence with sST2 or hsTnI, and none of the 3 biomarkers was significantly associated with mean CCA IMT. GDF-15 was a stronger predictor of maximal ICA thickness and plaque presence compared with BNP and CRP when these conventional biomarkers were tested together.
Increased GDF-15 concentrations are associated with subclinical atherosclerosis, including maximal ICA IMT and carotid plaque presence. Future studies investigating the role of GDF-15 for screening and management of patients with subclinical atherosclerosis are warranted.
[Show abstract][Hide abstract] 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(6). DOI:10.1160/TH14-02-0174 · 4.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
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.
C57Bl/6 mice underwent permanent coronary artery ligation. Serial PET imaging was performed 3 - 7 days after MI using (68)Ga-citrate, (68)Ga-DOTATATE, or (18)F-FDG with ketamine/xylazine suppression of myocyte glucose uptake. Myocardial perfusion was evaluated by (13)N-ammonia PET and cardiac geometry by contrast-enhanced ECG-gated CT.
Mice exhibited a perfusion defect of 30 - 40% (of the total left ventricle) with apical anterolateral wall akinesia and thinning on day 7 after MI. (18)F-FDG with ketamine/xylazine suppression demonstrated distinct uptake in the infarct region, as well as in the border zone and remote myocardium. The myocardial standardized uptake value in MI mice was significantly higher than in healthy mice under ketamine/xylazine anaesthesia (1.9 ± 0.4 vs. 1.0 ± 0.1). (68)Ga images exhibited high blood pool activity with no specific myocardial uptake up to 90 min after injection (tissue-to-blood contrast 0.9). (68)Ga-DOTATATE was rapidly cleared from the blood, but myocardial SUV was very low (0.10 ± 0.03).
Neither (68)Ga nor (68)Ga-DOTATATE is a useful alternative to (18)F-FDG for PET imaging of myocardial inflammation after MI in mice. Among the three tested approaches, (18)F-FDG with ketamine/xylazine suppression of cardiomyocyte uptake remains the most practical imaging marker of post-infarct inflammation.
European journal of nuclear medicine and molecular imaging 08/2014; 42(2). DOI:10.1007/s00259-014-2884-6 · 5.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms. METHODS: In this randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. RESULTS: The trial was stopped prematurely, according to prespecified rules, after a median follow-up period of 21 months. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008); 10.8% and 13.5%, respectively, died of cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001). CONCLUSIONS: Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (Funded by Pfizer; ClinicalTrials.gov number, NCT00232180.).
[Show abstract][Hide abstract] 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).
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)
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.
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. DOI:10.1016/j.ijcard.2014.01.025 · 4.04 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1016/j.ahj.2013.10.003 · 4.46 Impact Factor
[Show abstract][Hide abstract] 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; 101(3). DOI:10.1093/cvr/cvt275 · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective was to evaluate the hypothesis that growth-differentiation factor 15 (GDF-15) is an independent marker of the long-term risk for both cardiovascular disease and cancer morbidity beyond clinical and biochemical risk factors. Plasma obtained at age 71 was available from 940 subjects in the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort. Complete mortality and morbidity data were obtained from public registries. At baseline there were independent associations between GDF-15 and current smoking, diabetes mellitus, biomarkers of cardiac (high-sensitivity troponin-T, NT-proBNP) and renal dysfunction (cystatin-C) and inflammatory activity (C-reactive protein), and previous cardiovascular disease (CVD). During 10 years follow-up there occurred 265 and 131 deaths, 115 and 46 cardiovascular deaths, and 185 and 86 events with coronary heart disease mortality or morbidity in the respective total cohort (n=940) and non-CVD (n=561) cohort. After adjustment for conventional cardiovascular risk factors, one SD increase in log GDF-15 were, in the respective total and non-CVD populations, associated with 48% (95%CI 26 to 73%, p<0.001) and 67% (95%CI 28 to 217%, p<0.001) incremental risk of cardiovascular mortality, 48% (95%CI 33 to 67%, p<0.001) and 61% (95%CI 38 to 89%, p<0.001) of total mortality and 36% (95%CI 19 to 56%, p<0.001) and 44% (95%CI 17 to 76%, p<0.001) of coronary heart disease morbidity and mortality. The corresponding incremental increase for cancer mortality in the respective total and non-cancer disease (n=882) population was 46% (95%CI 21 to 77%, p<0.001) and 38% (95%CI 12 to 70%, p<0.001) and for cancer morbidity and mortality in patients without previous cancer disease 30% (95%CI 12 to 51%, p<0.001). In conclusion, in elderly men, GDF-15 improves prognostication of both cardiovascular, cancer mortality and morbidity beyond established risk factors and biomarkers of cardiac, renal dysfunction and inflammation.
PLoS ONE 12/2013; 8(12):e78797. DOI:10.1371/journal.pone.0078797 · 3.23 Impact Factor