Occurrence Of Secondary Events Research Articles

Renin and aldosterone are not associated with vulnerable plaque characteristics in patients with carotid artery disease

BackgroundThe renin-angiotensin-aldosterone system is increasingly being recognized to play an important role in the development and clinical course of cardiovascular diseases. Renin-angiotensin-aldosterone system activation is associated with clinical outcome in various populations of cardiovascular patients, such as patients with coronary artery, peripheral artery, and cerebrovascular disease. In this study, we investigated the associations between plasma renin and aldosterone concentrations and atherosclerotic plaque characteristics and secondary vascular events in patients undergoing carotid endarterectomy. Methods and ResultsBaseline plasma renin and aldosterone concentrations from 506 subjects undergoing carotid endarterectomy (mean age, 67 ± 9 years; 65% male) were correlated with histopathologic characteristics and inflammatory protein concentrations of the excised atherosclerotic plaque. Ordinal logistic regression (for ordinal outcome parameters) or linear regression (for linear outcome) analysis did not show a statistically significant relationship between plasma renin or aldosterone concentrations and plaque fat, thrombus, calcifications, collagen, smooth muscle cells, or macrophage content. Neither could any association be found with intraplaque inflammatory mediators. During a median follow-up of 3 years, 102 (20%) patients experienced a major secondary vascular event (composite of stroke, myocardial infarction, leg amputation, vascular death, or coronary revascularization or peripheral intervention). In multivariable Cox regression analysis, including both renin and aldosterone, baseline renin concentrations were associated with the occurrence of secondary events. ConclusionsIn patients with established atherosclerotic disease undergoing carotid endarterectomy, plasma renin and aldosterone concentrations were not associated with atherosclerotic plaque characteristics. Plasma renin concentration was positively associated with the occurrence of major secondary vascular events.

Risk Factors of Coronary Artery Disease in Secondary Prevention--Results from the AtheroGene--Study.

BackgroundRisk factors are important in cardiovascular (CV) medicine for risk stratification of patients. We aimed to compare the traditional risk factors to clinical variables for the prediction of secondary cardiovascular events.Methods and ResultsFor this study, 3229 patients with known coronary artery disease (CAD) were included. We calculated whether the traditional risk factors, diabetes mellitus, increased LDL/HDL ratio, arterial hypertension and smoking alone and in combination with the clinical variables, ejection fraction, creatinine clearance, multi-vessel disease and CRP concentration predict the outcome cardiovascular death or non-fatal myocardial infarction (N = 432) during the mean follow-up time of 4.2 ± 2.0 years. In this cohort diabetes mellitus was the risk factor with the strongest influence regarding occurrence of secondary events (hazard ratio; HR:1.70, confidence interval; CI 95%: 1.36-2.11; P<0.0001), followed by LDL/HDL ratio and smoking. However, risk stratification is further improved by using additional clinical variables like ejection fraction (HR:3.30 CI 95%:2.51-4.33; P>0.0001) or calculated creatinine clearence (Cockroft-Gault formula) (HR:2.26 CI 95%:1.78-2.89; P<0.0001). Further ameliorating risk stratification from the clinical variables were CRP and multi-vessel disease. The most precise risk prediction was achieved when all clinical variables were added to the CV risk factors.ConclusionDiabetes mellitus has the strongest influence to predict secondary cardiovascular events in patients with known CAD. Risk stratification can further be improved by adding CV risk factors and clinical variables together. Control of risk factors is of paramount importance in patients with known CAD, while clinical variables can further enhance prediction of events.

Decitabine (DAC) Treatment Induces Very Early In Vivo DNA Methylation and Transcriptome Changes in Primary AML Peripheral Blood Blasts

Abstract 1360 Background:The in vitro effects of the DNA hypomethylating agents 5-aza-C (5-azacytidine) and 5-aza-dC (DAC) upon the epigenome and transcriptome of AML cell lines have been investigated by numerous groups, demonstrating induction of gene-specific and global hypomethylation, as well as up- and downregulation of multiple genes. However, their in vivo mechanisms of action are not well-studied, with only very sparse data on primary blasts from patients (pts) with myeloid neoplasias treated with these compounds (Daskalakis et al., Blood 2002, Yang et al., Cancer Research 2006, Fandy et al., Blood 2009). This is primarily due to the substantial methodological challenges of obtaining sufficient cell numbers of bona fide malignant cells during treatment. To study very early in vivo effects, we isolated and analyzed primary cells from AML pts with high numbers of peripheral blood blasts treated with the hypomethylating agent DAC. Patients, Materials and Methods:Of 48 consecutive pts aged >60 years with newly diagnosed AML treated with DAC as described (Lübbert et al., 2011) at a single centre within a multicenter phase II study (trial 00331), successful sequential sampling of peripheral blood blasts in sufficient numbers and purity was feasible in 8 pts. The median WBC at AML diagnosis was 18,400/μl (range 4,800–241,000), the median age was 80 years, and 6/8 had cytogenetic abnormalities. The methylation state of LINE1 and 35 genes (5’ regions, represented by a total of 635 evaluable CpG dinucleotides) was quantified by MALDI-TOF mass spectrometry. Gene selection criteria were based on previous identification as potentially silenced tumor suppressors in genome-wide methylation analyses, and on reports as epigenetic targets in myeloid neoplasia. Transcriptional changes were assessed by array-based transcriptome profiling using the HG-U133plus 2.0 GeneChip array. Results:Isolation and purification of sufficient numbers of blasts was done both immediately before and at day 6 (median, range 4–7) after start of DAC infusion. Methylation quantification of pre-treatment blasts yielded patterns clearly distinguishing them from CD34-positive normal hematopoietic precursors of healthy donors (n=10). Specifically, P73, P15 and CDH1 exhibited the strongest and most consistent methylation gains (9–18%, p<0.015) in the malignant vs. normal cells. Early after DAC treatment, a striking decrease in LINE1 methylation was noted in 7/8 pts (p = 0.02), the most consistent effect among all investigated genomic regions. Overall, DAC-induced methylation changes (hypo- and/or hypermethylation) occurred in all eight pts. Hypomethylation was observed in the CpG islands of PBX1 (median 11%, range 5.5–25%, p<0.069), ESR1 (median 1.5%, range 0–9%, p<0.1) and MPO (median 4.3%, range 1–19%, p<0.1). For P73 and TLX3, substantial hypomethylation was observed in a subset of patients (maximum changes of 36% and 34% respectively), while other pts showed unchanged or increased DNA methylation levels. Unsupervised hierarchical clustering revealed that the highest similarities were intra- but not inter-individual. When interrogating unbiased methylation changes at all 635 CpGs, significant hypomethylation was induced in 4/8 pts, significant hypermethylation in 1/8 pts, and non-significant methylation changes seen in 3/8 pts. DAC-induced mRNA expression changes also occurred in all eight pts, without clear correlations between hypomethylation and restored expression. Conclusions:DAC administered at a clinically effective dose and schedule resulted in a consistent and pronounced in vivo decrease of LINE1 methylation already at early time points after treatment start, with significant hypomethylation events in 50% of the pts This might be indicative of effective, early Dnmt1 depletion. Induction of multiple transcriptional changes (but up- and downregulation) was also noted in all pts. This is, to the best of our knowledge, the first report of an integrated methylation/transcriptome analysis in primary leukemia cells isolated at very early time points during therapy with hypomethylating agents, i.e. before clonal selection or even replacement and the occurrence of secondary events. Our observations are compatible with a mechanism of action of DAC that is distinct from those of a non-hypomethylating cytosine analogues such as cytarabine, in line with in vitro results (Flotho et al, Leukemia 2009). Disclosures:No relevant conflicts of interest to declare.

Changes in cerebral interstitial glycerol concentration in head-injured patients; correlation with secondary events.

To investigate the association between the occurrence of secondary events, clinical outcome and the interstitial glycerol levels as measured with cerebral microdialysis. All patients received a ventriculostomy, a Camino pressure sensor and a CMA 70 microdialysis catheter. Intracranial pressure (ICP), cerebral perfusion pressure (CPP), blood pressure and arterial oxygen saturation (SaO2) were continuously monitored. Hourly microdialysis samples were collected and glycerol concentrations analyzed on-line. Glasgow Coma Score (GCS) scoring, blood gas and other laboratory analyses or investigations followed the routine of the intensive care unit. The Glasgow Outcome Scale (GOS) was assessed 6 months after injury. Intensive Care Unit and Department of Neurosurgery, VU University Hospital. Fifteen consecutive patients with severe traumatic brain injury and a GCS of 8 or less. No association was found between low CPP, high ICP, low PaCO2, low SaO2 or rise in temperature and the level of interstitial glycerol. In patients with a favorable outcome, the glycerol concentration never reached a level above 150 micromol/l, whereas a peak glycerol level above 150 micromol/l had a positive predictive value of 100% for an unfavorable outcome. The average of the area under the curve during the first 24 h of monitoring was significantly higher in the group with an unfavorable outcome (Kolmogorov-Smirnov test, p=0.044). Measuring interstitial glycerol for early detection of secondary adverse events, which possibly lead to secondary brain damage, does not seem useful. A peak level of interstitial glycerol above 150 micromol/l has a positive predictive value of 100% for an unfavorable outcome and hence indicates the severity of the parenchymal damage.