Abstract-Atherosclerotic cardiovascular disease results in Ͼ19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of

The uptake of pristine single-walled carbon nanotubes into macrophage-like cells has been studied using the nanotubes' intrinsic near-infrared fluorescence. Macrophage samples that have been incubated in growth media containing suspended single-walled nanotubes show characteristic nanotube fluorescence spectra. The fluorescence intensities increase smoothly with incubation time and external nanotube concentration. Near-infrared fluorescence microscopy at wavelengths above 1100 nm provides high contrast images indicating localization of nanotubes in numerous intracellular vesicles. Nanotube uptake appears to occur through phagocytosis. Population growth of macrophage cultures is unaffected by exposure to single-walled nanotube concentrations of ca. 4 mug/mL for up to 96 h.

Background-Bone marrow-derived stem cells are under investigation as a treatment for ischemic heart disease.Mesenchymal stem cells (MSCs) have been used preferentially in the acute ischemia model; data in the chronic ischemia model are lacking. Methods and Results-Twelve dogs underwent ameroid constrictor placement. Thirty days later, they received intramyocardial injections of either MSCs (100ϫ10 6 MSCs/10 mL saline) (nϭ6) or saline only (10 mL) (controls) (nϭ6). All were euthanized at 60 days. Resting and stress 2D echocardiography was performed at 30 and 60 days after ameroid placement. White blood cell count (WBC), C-reactive protein (CRP), creatine kinase MB (CK-MB), and troponin I levels were measured. Histopathological and immunohistochemical analyses were performed. Mean left ventricular ejection fraction was similar in both groups at baseline but significantly higher in treated dogs at 60 days. WBC and CRP levels were similar over time in both groups. CK-MB and troponin I increased from baseline to 48 hours, eventually returning to baseline. There was a trend toward reduced fibrosis and greater vascular density in the treated group. MSCs colocalized with endothelial and smooth muscle cells but not with myocytes. Conclusions-In

No abstract

We disrupted the FOG-2 gene in mice to define its requirement in vivo. FOG-2(-/-) embryos die at midgestation with a cardiac defect characterized by a thin ventricular myocardium, common atrioventricular canal, and the tetralogy of Fallot malformation. Remarkably, coronary vasculature is absent in FOG-2(-/-) hearts. Despite formation of an intact epicardial layer and expression of epicardium-specific genes, markers of cardiac vessel development (ICAM-2 and FLK-1) are not detected, indicative of failure to activate their expression and/or to initiate the epithelial to mesenchymal transformation of epicardial cells. Transgenic reexpression of FOG-2 in cardiomyocytes rescues the FOG-2(-/-) vascular phenotype, demonstrating that FOG-2 function in myocardium is required and sufficient for coronary vessel development. Our findings provide the molecular inroad into the induction of coronary vasculature by myocardium in the developing heart.

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

GATA-family transcription factors are critical to the development of diverse tissues. In particular, GATA-4 has been implicated in formation of the vertebrate heart. As the mouse Gata-4 knock-out is early embryonic lethal because of a defect in ventral morphogenesis, the in vivo function of this factor in heart development remains unresolved. To search for a requirement for Gata4 in heart development, we created mice harboring a single amino acid replacement in GATA-4 that impairs its physical interaction with its presumptive cardiac cofactor FOG-2. Gata4ki/ki mice die just after embryonic day (E) 12.5 exhibiting features in common with Fog2 −/− embryos as well as additional semilunar cardiac valve defects and a double-outlet right ventricle. These findings establish an intrinsic requirement for GATA-4 in heart development. We also infer that GATA-4 function is dependent on interaction with FOG-2 and, very likely, an additional FOG protein for distinct aspects of heart formation. Transcriptional activity of the GATA-factors is modulated through interaction with nuclear proteins, including zinc finger proteins of the Kruppel and FOG/Ushaped families, general coactivators (p300 and CBP), the myocardial-expressed protein Nkx2.5, and NF-AT3 (Durocher and Nemer 1998;Mackay and Crossley 1998;Blobel 2000;Molkentin 2000). Whereas the specificity and in vivo functional relevance of many of these interactions are incompletely defined, the association of GATA-1 with FOG-1 has been examined in detail. FOG-1 interacts with GATA-1 in hematopoietic cells and regulates the ability of GATA-1 to promote terminal differentiation of erythroid cells and megakaryocytes (Tsang et al. 1997). Mutation of specific residues within the conserved N-terminal zinc finger of GATA-1, such as V205G, disrupts binding to FOG-1, preserves DNA-binding properties of GATA-1, and renders GATA-1 unable to promote terminal differentiation of red blood cells (Crispino et al. 1999). Furthermore, mutation of Val 205 in humans leads to congenital dyserythropoietic anemia and thrombocytopenia (Nichols et al. 2000). Taken together, these findings demonstrate that direct physical association of GATA-1 and FOG-1 is essential for GATA-1's roles in transcription and, critical for the experiments reported herein, identifies a specific residue of the N finger that mediates cofactor interaction.GATA-4, GATA-5, and GATA-6, nonhematopoietic expressed factors, are implicated in development of heart, endoderm, and intestinal epithelia, where they are expressed in an overlapping and dynamic fashion Bossard and Zaret 1998;Gao et al. 1998;Koutsourakis et al. 1999;Parmacek and Leiden 1999;Molkentin 2000). GATA-4 has been extensively studied in the context of heart development, as it is present in precardiac splanchnic mesoderm and binds to and activates promoters and enhancers of numerous myocardial-expressed genes . In its absence, mouse embryos die by E7.0-9.5, with failure of ventral morphogenesis leading to cardiac bifida (Kuo et al. 1997;Molkentin et al. 1997). The deat...

Inflammatory diseases of the aorta include routine atherosclerosis, aortitis, periaortitis, and atherosclerosis with excessive inflammatory responses, such as inflammatory atherosclerotic aneurysms. The nomenclature and histologic features of these disorders are reviewed and discussed. In addition, diagnostic criteria are provided to distinguish between these disorders in surgical pathology specimens. An initial classification scheme is provided for aortitis and periaortitis based on the pattern of the inflammatory infiltrate: granulomatous/giant cell pattern, lymphoplasmacytic pattern, mixed inflammatory pattern, and the suppurative pattern. These inflammatory patterns are discussed in relation to specific systemic diseases including giant cell arteritis, Takayasu arteritis, granulomatosis with polyangiitis (Wegener's), rheumatoid arthritis, sarcoidosis, ankylosing spondylitis, Cogan syndrome, Behçet's disease, relapsing polychondritis, syphilitic aortitis, and bacterial and fungal infections.