Day: 03/27/2011

Epicardial Adipose Tissue: An Emerging Role for the Development of Coronary Atherosclerosis

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There is a growing body of evidence that epicardial adipose tissue (EAT) plays an enhancing role in the development of coronary atherosclerosis.1,2 Pericardial fat is deposited around the heart at two locations, as epicardial and paracardial adipose tissue separated from each other by the parietal pericardium. Paracardial adipose tissue originates from the primitive thoracic mesenchyme and is supplied by the pericardiophrenic artery, a branch of the internal thoracic artery. EAT is defined as adipose tissue situated within the pericardium. EAT originates from the splanchnopleuric mesoderm (such as the mesenteric and omental fat deposits), and the vascular supply is from coronary arteries. Conceptually, EAT is more interesting than paracardial adipose tissue because of the close anatomic relationship between EAT and the myocardium. EAT also includes peri-coronary fat situated around the coronary arteries, which may even be more appealing due to its very close proximity to the coronary arteries, suggesting a role for the development of coronary atherosclerosis. So far there is no general consensus as to which of these fat deposits should be studied, but most reports are about EAT, and few also report about the peri-coronary fat deposits.1,2 EAT is metabolically active visceral fat, and the quantity of EAT is correlated with the metabolic syndrome (a waist circumference, hypertriglyceridemia, and hyperglycemia), cardio-metabolic risk factors, and coronary atherosclerosis.2 EAT is distributed asymmetrically around the heart, and the fat is deposited mainly at the atrioventricular and interventricular grooves, around the major coronary arteries and free wall of the right ventricle, and the apex of the left ventricle. EAT can be measured by magnetic resonance imaging or echocardiography, but recently computed tomography (CT) has emerged as a robust, 3-dimensional, high-resolution imaging technique that reliably identifies EAT. CT allows quantification of EAT by manually tracing the pericardium on cross-sectional CT images. Within the traced region, the adipose tissue is identified by voxels that have a range of −190 to −30 HU. Automated computer-assisted methods allow quantification of epicardial fat tissue measurements.

The measurements are presented as regional fat thickness (mm), as cross-sectional area (cm2), and as a volume (cm3). EAT volume is reported as ranging from 68 to 124 cm3. The volume of EAT accounts for approximately 15% to 20% of the total cardiac volume and covers approximately 80% of the total cardiac surface. EAT accounts for roughly 1% of the total body fat mass. EAT volume is higher in patients with a high body mass index (BMI) than in patients with a low BMI. The mean EAT thickness measured at several sites, including the free right ventricular wall, left ventricular anterior wall, and grooves was 5.3 ± 1.6 mm.1 The measurement of regional fat thickness around the coronary arteries is useful because it may reflect region-specific fat characteristics that may affect coronary atherosclerosis. The mean coronary peri-vascular adipose tissue thickness is 10.9 ± 1.9 mm in patients referred for invasive coronary angiography. CT scanning allows for the identification of coronary calcium, obstructive disease of the coronary arteries, and pericardial fat. Thus, CT scanning permits the establishment of a potential relationship between EAT and the quantity of coronary calcium and the magnitude of the coronary plaque burden, which may then be linked to the occurrence of adverse coronary events. In this issue of Clinical Cardiology, Iwasaki et al reported on the relationship between EAT, the calcium score, and the severity of coronary atherosclerosis.3 They studied 197 patients who underwent CT calcium scoring and 64-slice CT coronary angiography. In all of these patients they carefully measured the volume of EAT using a dedicated off-line postprocessing program. They found a significant correlation between the volume of EAT and the magnitude of the calcium score. In patients with EAT <100 mL, the calcium score was significantly lower than the score in patients with EAT volume >100 mL (175 ± 395 vs 384 ± 782 (P = 0.0016)). The presence of severe coronary artery disease (CAD) (≥50% diameter stenosis) was also significantly higher in patients with EAT volume >100 mL compared to patients with EAT volume <100 mL (40.2% vs 22.7% (P = 0.008)). The amount of EAT was significantly higher in patients with a high calcium score (>400) and severe coronary artery obstructive disease.

This study confirms and extends earlier studies that also demonstrated a positive relationship between EAT and the severity of CAD. The pathophysiologic significance of EAT in the development of coronary atherosclerosis is gradually evolving, and it is thought that peri-vascular adipose tissue adjacent to the coronary vessel wall may enable diffusion or transportation via the vaso vasorum of proinflammatory cytokines and adipokines produced by the adipocytes that may enhance the development of coronary atherosclerosis. It has been shown that these cytokines and adipokines are expressed and secreted at a higher level in the adipose tissue of patients with CAD than in patients without CAD.2 Indirect evidence for the atherogenic role of EAT is given by the fact that the absence of peri-vascular coronary fat, as occurs in coronary segments with myocardial bridges or segments with intramyocardial course, is associated with the absence of coronary atherosclerosis. Furthermore, preliminary studies have reported that EAT is associated with incident coronary heart disease, independent of BMI and cardiac risk factors, and the occurrence of adverse coronary events, suggesting that EAT is one of the factors contributing to coronary atherosclerosis.4,5 However, further studies are needed to unravel the pathophysiologic mechanisms of EAT. Large-sized studies should indicate that EAT is independently and incrementally associated with coronary atherosclerosis and is not confounded by the effects of abdominal adipose tissue and thus with obesity-associated systemic effects.

So far only cross-sectional studies have shown that the amount of EAT volume as well as the thickness of peri-vascular adipose tissue are associated with CAD. Long-term studies are lacking that establish whether EAT is an independent predictor of adverse coronary events.

Finally, the standardization of EAT thickness and cross-sectional or volume measurements obtained by CT are necessary to allow comparison of the studies.

source: wiley online library(cadiology)

New front against TNF

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New York University School of Medicine researchers have designed a molecule based on the growth factor progranulin that could help treat rheumatoid arthritis and other autoimmune diseases.1 The team has formed a company, ATreaon, to develop the compound and related analogs.

Previous work has suggested roles for progranulin (PGRN) in cancer,2 inflammation,3 host defense,4 cartilage development and degeneration5 and neurological functions.6, 7 However, using or targeting the molecule has been difficult because its receptors remained unknown.

Now, Chuan-ju Liu and colleagues at NYU have found that PGRN binds tumor necrosis factor receptors (TNFRs) and blocks their interactions with tumor necrosis factor-α (TNF-α), thus halting inflammatory signaling.

Liu is an associate professor at the NYU School of Medicine.

In a yeast two-hybrid screen using PGRN as bait, the team identified tumor necrosis factor receptor 1 (TNFRSF1A; TNFR1; CD120a) and TNFR2 as the main binding proteins for PGRN. The group confirmed the association through coimmunoprecipitation experiments in human chondrocytes.

In a mouse model of collagen-induced arthritis, knocking out Pgrn caused the development of more severe arthritis with bone and joint destruction, more rapid disease onset, greater disease incidence and higher levels of bone-resorbing osteoclasts than those in wild-type littermate controls.

The group also showed that administration of recombinant human PGRN (rhPGRN) to the knockouts blocked disease progression and prevented symptoms of inflammatory arthritis including synovitis, pannus formation, tissue destruction and loss of cartilage compared with administration of saline.

The findings were replicated in a mouse model of inflammatory arthritis induced by transgenic expression of TNF-α.

With the help of Cytovance Biologics LLC, a contract biologics manufacturer, the NYU team developed a molecule called Atsttrin (Antagonist of TNF/TNFR Signaling via Targeting to TNF Receptors), which includes parts of three granulin (GRN) domains from progranulin as well as three of the protein’s linker regions. Despite its smaller size, Atsttrin retains the functionality of PGRN on TNF receptors.

Compared with the parent molecule, Atsttrin also was more selective for the two TNFRs than for other closely related receptors.

Atsttrin also had higher affinity for TNFR2 than TNFR1—a finding that Martin Bachmann, CSO and EVP at Cytos Biotechnology AG, said needs to be further probed. “The fact that the molecule has a higher affinity for TNFR2 than TNFR1 may change its therapeutic properties compared with mAbs against TNF,” he said. “This may or may not be beneficial.”

Cytos’ CYT020-TNFQb, a vaccine that binds TNF-α and was developed with the company’s Immunodrug platform, is in preclinical testing to treat inflammation.

In the collagen-induced arthritis mouse model, Atsttrin decreased disease severity and delayed onset and progression better than rhPGRN; in a collagen antibody–induced arthritis mouse model, Atsttrin was more effective at treating inflammation than both rhPGRN and Enbrel etanercept, a soluble TNF receptor marketed by Amgen Inc.,Pfizer Inc. and Takeda Pharmaceutical Co. Ltd. for RA and a variety of other autoimmune indications.

“The unique anti-inflammatory mechanism of action of Atsttrin [means it] may be effective for those patients who do not respond to current TNF inhibitor treatments.”

Atsttrin was well absorbed via intraperitoneal administration and had high stability and a half-life of about five days.

The findings were published in Science. The paper also included researchers from Shandong University School of Medicine, Weill Cornell Medical College, Yale School of Medicine, Nankai University and Texas A&M Health Science Center.

In the fall of 2010, Jeffrey Su and colleagues formed ATreaon to develop Atsttrin and related compounds.

Su is CSO at Cytovance, which has not invested in the new compound but is a potential service provider to make the molecule.

ATreaon has raised an undisclosed amount of seed money and used the funds to license Atsttrin from the university and to develop analogs. The company hopes to put its lead compound into the clinic in the next 12 months for an autoimmune indication and is in talks with VCs and private equity investors to secure funding for IND-enabling studies, GMP manufacturing and clinical studies.

Liu told SciBX that Atsttrin could be developed for multiple TNF-associated conditions and pathologies including systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ankylosing spondylitis, plaque psoriasis and psoriatic arthritis.

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Room in the sandbox

Although the market for TNF modulators is crowded—there are five marketed biologics that block TNF—ATreaon thinks its product initially could be used behind those drugs or in the about 50% of RA patients who do not respond to them.

“The unique anti-inflammatory mechanism of action of Atsttrin [means it] may be effective for those patients who do not respond to current TNF inhibitor treatments,” said Su.

“It will also be quite interesting to find out whether this strategy can be used as an early intervention to prevent progression of symptoms or whether it works as an agent to use once other options have failed. I could imagine Atsttrin having both uses,” said Andrew Bateman, a professor in the Department of Medicine at McGill University. “It will also be interesting to find out whether Atsttrin can be used along with conventional agents in combination therapy.”

Bateman’s research on the role of PGRN in wound healing showed that the protein promotes repair and regeneration of damaged tissues. “One could imagine that progranulin or an analog could repair the tissue damaged during the course of disease once the inflammation is under control,” he said. “TNF has a lot of effects on immune responses and is a major switch for inflammation. TNF is not a bad thing, but it is a problem when it gets out of control and can be very dangerous. Rather than squishing it completely and blocking its beneficial functions, the goal is to be able to bring it back to a healthy range. It will be interesting to see if progranulin or related analogs can bring it back down to appropriate levels. This will take a lot of tuning to get the conditions right.”

“It will also be interesting to find out whether Atsttrin can be used along with conventional agents in combination therapy.”

Andrew Bateman
McGill University

In terms of safety, Aihao Ding, professor in the Department of Microbiology and Immunology at Weill Cornell, thinks Atsttrin could enjoy an advantage over anti-TNF antibodies.

“One assumes Atsttrin would have fewer side effects because this is a small protein and not an antibody,” she said. “Antibodies can have more side effects because they can form new complexes in the blood stream” that can either lead to unwanted activation of cytokines or to immune suppression that increases susceptibility to serious infections.

Liu added that Atsttrin should not induce unwanted immune reactions because it is derived from a natural protein.

Bachmann, however, thinks that Atsttrin has been so heavily modified that it could be more immunogenic than mAbs. He also noted that “there is really no reason to believe that the elevated risk of infection associated with other autoimmune disease treatments will be reduced by Atsttrin because, at the end of the day, you still block TNF.”

Koh Ono, associate professor in the Department of Cardiovascular Medicine at Kyoto University, noted that “progranulin was first identified as a tumor growth factor. Therefore, Atsttrin or progranulin need to be carefully given to RA patients with cancer.”

“There is a worry that progranulin is a growth factor, and the question of whether it can cause cancer or not has not been tested,” Ding agreed. “But Atsttrin is a truncated form with the C terminal that is responsible for the growth factor effect removed, so the risk probably shouldn’t be there anymore.”

A final advantage that Atsttrin could have over the anti-TNF biologics is in cost of manufacturing. Liu told SciBX that Atsttrin is produced in bacteria, which he said should be cheaper than antibodies.

Su told SciBX that the currently available TNF blockers are complex molecules produced by mammalian cell culture via recombinant DNA technologies, which cost hundreds to thousands of dollars per gram of product to manufacture. He said that the manufacturing cost of Atsttrin-related compounds can be as low as 10%–20% of the cost of TNF blockers produced in animal cells.

According to Laurent Galibert, head of inflammation and metabolic disorders at Addex Pharmaceuticals Ltd., a key consequence of the high cost of production, and thus the high price tag for anti-TNF antibodies, is that the drugs “are not used as a first-line therapy even though from a purely scientific standpoint they should be.”

Addex has a small molecule TNFR1 negative allosteric modulator in the discovery stage to treat Alzheimer’s disease (AD), multiple sclerosis (MS), RA, psoriasis and depression.

source: nature immunology

Proliferative drive and liver carcinogenesis: Too much of a good thing?

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There have been innumerable studies published in the attempt to identify gene expression signatures in hepatocellular carcinoma (HCC). When all the regulators and targets of the differentially expressed genes are analyzed from larger studies, the most striking theme is upregulation of mitosis-promoting and cell proliferation genes in HCC compared with ‘liver-specific gene clusters’ in non-tumorous tissue. A major limitation of expression profiling is that it only provides a ‘snapshot’ of what is an evolving process and thus cannot distinguish the differences in gene expression that are primary effectors of dysregulated growth from those that represent downstream consequences. The development of HCC in a chronically diseased liver, often referred to as hepatocarcinogenesis, is a multistep process characterized by the progressive accumulation and interplay of genetic alterations causing aberrant growth, malignant transformation of liver parenchymal cells, followed by vascular invasion and metastasis. This review will discuss HCC precursor lesions, draw on the ‘proliferation cluster’ genes highlighted from HCC expression profiling studies, relate them to a selection of regulatory networks important in liver regeneration, cell cycle control and their potential significance in the pathogenesis of HCC or primary liver cancer.

source: wiley online library

Bone marrow stem cells and the liver: Are they relevant?

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The contribution of bone marrow stem cell responses to liver homeostasis, injury and malignancy is discussed in this review. Pluripotent stem cells or their more committed progenitor progeny are essential to tissue development, regeneration and repair and are widely implicated in the pathogenesis of malignancy. Stem cell responses to injury are the focus of intense research efforts in the hope of future therapeutic manipulation. Stem cells occur within tissues, such as the liver, or arise from extrahepatic sites, in particular, the bone marrow. As the largest reservoir of stem cells in the adult, the bone marrow has been implicated in the stem cell response associated with liver injury. However, in liver injury, the relative contribution of bone marrow stem cells compared to intrahepatic progenitor responses is poorly characterized. Intrahepatic progenitor responses have been recently reviewed elsewhere. In this review, we have summarized liver-specific extrahepatic stem cell responses originating from the bone marrow. The physiological relevance of bone marrow stem cell responses to adult liver homeostasis, injury and malignancy is discussed with emphasis on mechanisms of bone marrow stem cell recruitment to sites of liver injury and its contribution to intrahepatic malignancy.

source: wiley online libray

Role and significance of focal adhesion proteins in hepatocellular carcinoma

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Focal adhesions are structural links between the extracellular matrix and actin cytoskeleton. They are important sites where dynamic alterations of proteins in the focal contacts are involved during cell movement. Focal adhesions are composed of diverse molecules, for instance, receptors, structural proteins, adaptors, GTPase, kinases and phosphatases. These molecules play critical roles in normal physiological events such as cellular adhesion, movement, cytoskeletal structure and intracellular signaling pathways. In cancers, aberrant expression and altered functions of focal adhesion proteins contribute to adverse tumor behavior. It is evident that these proteins do not function alone, but rather associate and work together in the process of tumor development and cancer metastasis. Focal adhesion proteins have been shown to play critical roles in hepatocellular carcinoma. Understanding the molecular interactions and mechanisms of the interconnected focal adhesion proteins is of particular importance in understanding mechanisms underlying hepatocellular carcinoma progression and development of potential effective treatment.

source: wiley online library

Intestinal metaplasia: A premalignant lesion involved in gastric carcinogenesis

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Despite a plateau in incidence, gastric cancer remains a significant problem globally. The majority of gastric cancer is associated with histologically recognizable premalignant stages as first described by Pelayo Correa in the mid-1970s. The mortality from gastric cancer remains high especially in Western countries where, arguably, the index of suspicion of gastric cancer in patients presenting with upper abdominal symptoms is lower than in high prevalence countries. What is the evidence that intestinal metaplasia (IM) is a premalignant condition? What should the clinician know about IM and the relative risks of progression to gastric cancer? Finally, what are the current and future strategies that may help stratify patients into high risk and low risk for the development of gastric cancer? This review focuses on gastric IM and outlines some of the literature that discusses it as a premalignant condition. It also reviews the issue of surveillance of patients with IM in order to attempt to reduce the significant mortality of gastric cancer by detection of earlier stages of disease which are eminently treatable.

source: wiley online library

An ARB for Hypertensive Patients with Acute Stroke?

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The angiotensin-receptor blocker candesartan didn’t improve outcomes.

In patients with acute ischemic stroke, guidelines recommend withholding antihypertensive treatment until systolic blood pressure exceeds 220 mm Hg or diastolic BP exceeds 120 mm Hg . A slightly lower threshold (180–200 mm Hg) is recommended in patients with hemorrhagic stroke . However, hard evidence is lacking to support any particular threshold.

In this randomized European trial, 2000 patients with acute stroke (86% ischemic; 14% hemorrhagic) and systolic BP >140 mm Hg received 7-day courses of either placebo or the angiotensin-receptor blocker candesartan (Atacand; dose titrated to 16 mg, if necessary). Mean BP at enrollment was 171/90 mm Hg; during treatment, mean systolic BP averaged 3 to 5 mm Hg lower with candesartan than with placebo.

During the 7-day treatment phase, neurological status (according to a standardized stroke scale) was similar in the candesartan and placebo groups, but 6-month functional status was marginally worse in the candesartan group (P=0.05). At 6 months, a primary composite vascular endpoint (stroke, myocardial infarction, vascular death) had occurred with similar frequency in the two groups. Candesartan therapy did not benefit patients with the highest baseline systolic BPs (i.e., >180 or >200 mm Hg) or patients with hemorrhagic strokes.

Comment: Candesartan does not improve outcomes in patients with acute stroke. Note, however, that this trial hardly tested the effect of BP lowering, given the difference of only 3 to 5 mm Hg systolic BP between groups. The researchers postulated that candesartan might confer benefit both through lowering BP and through non–BP-related neuroprotective mechanisms, but that didn’t happen. Clinicians should follow the above-referenced guidelines, unless future studies generate persuasive evidence to lower treatment thresholds.

Source:Journal Watch General Medicine