Background-Circulating cardiac troponin T, a marker of cardiomyocyte injury, predicts adverse outcome in patients with heart failure (HF) but is detectable in only a small fraction of those with chronic stable HF. We assessed the prognostic value of circulating cardiac troponin T in patients with stable chronic HF with a traditional (cTnT) and a new precommercial highly sensitive assay (hsTnT). Methods and Results-Plasma troponin T was measured in 4053 patients with chronic HF enrolled in the Valsartan HeartFailure Trial (Val-HeFT). Troponin T was detectable in 10.4% of the population with the cTnT assay (detection limit Յ0.01 ng/mL) compared with 92.0% with the new hsTnT assay (Յ0.001 ng/mL). Patients with cTnT elevation or with hsTnT above the median (0.012 ng/mL) had more severe HF and worse outcome. In Cox proportional hazards models adjusting for clinical risk factors, cTnT was associated with death (780 events; hazard ratioϭ2. Key Words: heart failure Ⅲ natriuretic peptides Ⅲ prognosis Ⅲ troponin C ardiac troponins I and T (cTnT) are sensitive and specific markers of myocardial injury used routinely for the diagnosis of acute coronary syndromes. 1-5 Elevated troponin blood levels have been reported in several cohorts of patients with heart failure (HF), and the magnitude of elevation has been correlated with the severity of the disease and with adverse outcomes. 6 -16 Because of their high cardiac specificity, elevated troponins in patients with HF may suggest ongoing myocardial damage and may serve as a marker for the progression of HF. Measurement of troponin has been proposed since 1997 to monitor patients with HF. 17,18 The prevalence of elevated troponin T in the general population is Ͻ1% and is associated with underlying cardiovascular disease or high-risk phenotypes. 19 Editorial p 1217 Clinical Perspective p 1249The levels of cardiac troponins in HF are generally lower than those in patients with acute coronary syndromes and lack the characteristic rise and fall pattern. 4 Few reports exist on cTnT elevations in chronic stable HF. 6,8,16,20 Previous studies included more frequently patients with severe HF (New York Heart Association [NYHA] class III and IV) and/or with decompensated HF, recruited in a single center. 6,8,10,11,15,16 As expected, lesser severity of HF is associated with a larger fraction of patients with undetectable troponin. The commercial assays for troponins have sufficient sensitivity (0.01 ng/mL) for screening patients with suspected myocardial infarction 21 but may be inadequate for risk stratification of patients with stable chronic HF who may have levels below Methods Study Design and PatientsVal-HeFT was a randomized, placebo-controlled, double-blind, parallel-arm multicenter trial of 5010 patients with stable, symptomatic HF, who were on prescribed HF therapy. The patients had a left ventricular ejection fraction (LVEF) Ͻ40% and a left ventricular diameter in diastole adjusted for body surface area (LVIDD/BSA) Ն2.9 cm/m 2 . Results of the main trial have been published....

Pancreatic ductal adenocarcinoma (PDA) remains one of the deadliest forms of cancer, in part, because it is largely refractory to current therapies. The failure of most standard therapies in PDA, as well as promising immune therapies, may be largely ascribed to highly unique and protective stromal microenvironments that present significant biophysical barriers to effective drug delivery, that are immunosuppressive, and that can limit the distribution and function of antitumor immune cells. Here, we utilized stromal reengineering to disrupt these barriers and move the stroma toward normalization using a potent antifibrotic agent, halofuginone. In an autochthonous genetically engineered mouse model of PDA, halofuginone disrupted physical barriers to effective drug distribution by decreasing fibroblast activation and reducing key extracellular matrix elements that drive stromal resistance. Concomitantly, halofuginone treatment altered the immune landscape in PDA, with greater immune infiltrate into regions of low hylauronan, which resulted in increased number and distribution of both classically activated inflammatory macrophages and cytotoxic T cells. In concert with a direct effect on carcinoma cells, this led to widespread intratumoral necrosis and reduced tumor volume. These data point to the multifunctional and critical role of the stroma in tumor protection and survival and demonstrate how compromising tumor integrity to move toward a more normal physiologic state through stroma-targeting therapy will likely be an instrumental component in treating PDA. Significance: This work demonstrates how focused stromal re-engineering approaches to move toward normalization of the stroma disrupt physical barriers to effective drug delivery and promote antitumor immunity. See related commentary by Huang and Brekken, p. 328

cTnI increases are encountered in approximately a third of patients, the majority due to nonatherothrombotic conditions. Compared with patients without myonecrosis, type 2 myocardial infarction and myocardial injury have worse short-term outcomes, with mortality rates >20% at 2 years. hs-cTnI assay does not lead to more myocardial injury or infarction.

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Rationale Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche following acute myocardial infarction (AMI). Objective To study the BM composition in patients with IHD and severe left ventricular dysfunction (LVD). Methods & Results BM from 280 patients with IHD and LVD were analyzed for cell subsets by flow cytometry and colony assays. BM CD34+ cell percentage was decreased 7 days after AMI (mean of 1.9% vs. 2.3-2.7% in other cohorts; p< 0.05). BM-derived endothelial colonies were significantly decreased (p< 0.05). Increased BM CD11b+ cells associated with worse left ventricular ejection fraction (LVEF) after AMI (p< 0.05). While increased BM CD34+ percentage associated with greater improvement in LVEF (+9.9% vs. +2.3%, p=0.03, for AMI patients; and +6.6% vs. -0.02%, p=0.021 for chronic IHD patients), decreased BM CD34+ percentage in chronic IHD patients correlated with decrement in LVEF after cell therapy (-2.9% vs. +0.7%, p=0.0355). Conclusions In this study we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir seven days after AMI, a negative correlation between CD11b percentage and post-infarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and/or reversal of co-morbid BM impairment.

A large-scale functional genomics project was initiated to study the function of chromatin-related genes in maize (Zea mays). Transgenic lines containing short gene segments in inverted repeat orientation designed to reduce expression of target genes by RNA interference (RNAi) were isolated, propagated, and analyzed in a variety of assays. Analysis of the selectable marker expression over multiple generations revealed that most transgenes were transmitted faithfully, whereas some displayed reduced transmission or transgene silencing. A range of target-gene silencing efficiencies, from nondetectable silencing to nearly complete silencing, was revealed by semiquantitative reverse transcription-PCR analysis of transcript abundance for the target gene. In some cases, the RNAi construct was able to cause a reduction in the steady-state RNA levels of not only the target gene, but also another closely related gene. Correlation of silencing efficiency with expression level of the target gene and sequence features of the inverted repeat did not reveal any factors capable of predicting the silencing success of a particular RNAi-inducing construct. The frequencies of success of this large-scale project in maize, together with parameters for optimization at various steps, should serve as a useful framework for designing future RNAi-based functional genomics projects in crop plants.

Objective-The goal of this study was to test the contributing role of increasing glucose uptake in vascular smooth muscle cells (VSMCs) in vascular complications and disease. Methods and Results-A murine genetic model was established in which glucose trasporter 1 (GLUT1), the non-insulindependent glucose transporter protein, was overexpressed in smooth muscle using the sm22␣ promoter. Overexpression of GLUT1 in smooth muscle led to significant increases in glucose uptake (nϭ3, PϽ0.0001) as measured using radiolabeled 2-deoxyglucose. Fasting blood glucose, insulin, and nonesterified fatty acids were unchanged. Contractility in aortic ring segments was decreased in sm22␣-GLUT1 mice (nϭ10, PϽ0.04). In response to vascular injury, sm22␣-GLUT1 mice exhibited a proinflammatory phenotype, including a significant increase in the percentage of neutrophils in the lesion (nϭ4, PϽ0.04) and an increase in monocyte chemoattractant protein-1 (MCP-1) immunofluorescence. Circulating haptoglobin and glutathione/total glutathione were significantly higher in the sm22␣-GLUT1 mice postinjury compared with controls (nϭ4, PϽ0.05), suggesting increased flux through the pentose phosphate pathway. sm22␣-GLUT1 mice exhibited significant medial hypertrophy following injury that was associated with a significant increase in the percentage of VSMCs in the media staining positive for nuclear phosphoSMAD2/3 (nϭ4, PϽ0.003). Conclusion-In summary, these findings suggest that increased glucose uptake in VSMCs impairs vascular contractility and accelerates a proinflammatory, neutrophil-rich lesion in response to injury, as well as medial hypertrophy, which is associated with enhanced transforming growth factor-␤ activity. Key Words: Glut1 Ⅲ hypertrophy Ⅲ vascular smooth muscle Ⅲ haptoglobin Ⅲ phosphoSMAD2/3 Ⅲ glucose Ⅲ neutrophil Ⅲ macrophage C ardiovascular complications remain the number one cause of death from individuals with diabetes. Epidemiological studies to date have reported conflicting results over the role of glucose as a contributing risk factor to coronary artery disease in individuals with type 1 diabetes. 1-9 A recent report found that glycohemoglobin in nondiabetic adults was strongly associated with coronary artery disease, further suggesting that increasing cellular glucose uptake promotes vascular complications and coronary artery disease. 10 However, the mechanisms through which glucose increases the risk of coronary artery disease are not well understood. Specifically, the role of increasing glucose uptake in different cell types in contributing to coronary artery disease is not well understood.We tested the hypothesis that increasing glucose uptake in vascular smooth muscle cells would alter the contractility properties of the vessel. In addition, we tested the hypothesis that in response to vascular injury, increased glucose uptake would exacerbate vascular intima formation.We used a genetic approach to increase expression of the non-insulin-dependent glucose transporter protein GLUT1 in VSMCs using the sm22␣ promoter. This...

ICD-9-coded MIs captured only a small proportion of adjudicated MIs, primarily from not coding T2MI. Our findings emphasize the need for an ICD code for T2MI.