Lea Sarov-Blat

Treatment Research Institute, Philadelphia PA, Philadelphia, Pennsylvania, United States

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Publications (18)106.11 Total impact

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    ABSTRACT: Background p38 MAPK inhibition has potential myocardial protective effects. We assessed losmapimod, a potent oral p38 MAPK inhibitor, in patients with non-ST-segment elevation myocardial infarction (NSTEMI) in a double-blind, randomised, placebo-controlled trial. Methods From October, 2009, to November, 2011, NSTEMI patients were assigned oral losmapimod (7·5 mg or 15·0 mg loading dose followed by 7·5 mg twice daily) or matching placebo in a 3:3:2 ratio. Safety outcomes were serious adverse events and alanine aminotransferase (ALT) concentrations over 12 weeks, and cardiac events (death, myocardial infarction, recurrent ischaemia, stroke, and heart failure) at 90 days. Efficacy outcomes were high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP) concentrations at 72 h and 12 weeks, and troponin I area under the curve (AUC) over 72 h. The losmapimod groups were pooled for analysis. This trial is registered with ClinicalTrials.gov, number NCT00910962. Findings Of 535 patients enrolled, 526 (98%) received at least one dose of study treatment (losmapimod n=388 and placebo n=138). Safety outcomes did not differ between groups. HsCRP concentrations at 72 h were lower in the losmapimod group than in the placebo group (geometric mean 64·1 nmol/L, 95% CI 53·0–77·6 vs 110·8 nmol/L, 83·1–147·7; p=0·0009) but were similar at 12 weeks. Early geometric mean BNP concentrations were similar at 72 h but significantly lower in the losmapimod group at 12 weeks (37·2 ng/L, 95% CI 32·3–42·9 vs 49·4 ng/L, 38·7–63·0; p=0·04). Mean troponin I AUC values did not differ. Interpretation p38 MAPK inhibition with oral losmapimod was well tolerated in NSTEMI patients and might improve outcomes after acute coronary syndromes. Funding GlaxoSmithKline.
    Lancet. 01/2014;
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    ABSTRACT: Genetics can be used to predict drug effects and generate hypotheses around alternative indications. To support Losmapimod, a p38 mitogen-activated protein kinase inhibitor in development for acute coronary syndrome, we characterized gene variation in MAPK11/14 genes by exome sequencing and follow-up genotyping or imputation in participants well-phenotyped for cardiovascular and metabolic traits.
    Journal of the American Heart Association. 01/2014; 3(4).
  • Journal of the American College of Cardiology 08/2013; · 14.09 Impact Factor
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    ABSTRACT: AIM: The purpose of this study was to establish safety and tolerability of a single intravenous (IV) infusion of a p38 MAP-kinase inhibitor, losmapimod, to obtain therapeutic levels rapidly for a potential acute coronary syndrome (ACS) indication. Pharmacokinetics (PK) following IV dosing were characterized and pharmacokinetic/pharmacodynamic (PK/PD) relationships between losmapimod and pHSP27 and hsCRP were explored. METHODS: Healthy volunteers received 1mg losmapimod IV over 15 minutes (n=4) or 3mg IV over 15 minutes followed by a washout period and then 15mg orally (PO) (n=12). PK parameters were calculated by non-compartmental methods. PK/PD relationships were explored using modelling and simulation. RESULTS: There were no deaths, non-fatal SAEs, or AEs leading to withdrawal. Headache was the only AE reported more than once, n=3 following oral dosing. Following 3mg IV and 15 mg PO, Cmax was 59.4 μg/L and 45.9 μg/L and AUC(0-inf) was 171.1 μg·hr/L and 528.0 μg·hr/L, respectively. Absolute oral bioavailability was 0.62 (90% CI 0.56, 0.68). Following 3mg IV and 15mg PO, maximum reductions in pHSP27 were 44% (95% CI 38%, 50%) and 55% (95% CI 50%, 59%) occurring at 30 minutes and 4 hours, respectively. There was a 17% decrease (95% CI 9%, 24%) in hsCRP 24 hours following oral dosing. A direct link maximum-inhibitory effect model related plasma concentrations to pHSP27 concentrations.. CONCLUSIONS: A single IV infusion of losmapimod in healthy volunteers was safe and well tolerated, and may potentially serve as an initial loading dose in ACS as rapid exposure is achieved.
    British Journal of Clinical Pharmacology 12/2012; · 3.69 Impact Factor
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    ABSTRACT: The p38 mitogen-activated protein kinase (MAPK) is a nexus point in inflammation, sensing, and stimulating cytokine production and driving cell migration and death. In acute coronary syndromes, p38MAPK inhibition could stabilize ruptured atherosclerotic plaques, pacify active plaques, and improve microvascular function, thereby reducing infarct size and risk of subsequent cardiac events. The SOLSTICE trial is randomized, double-blind, placebo-controlled, parallel group, multicenter phase 2a study of 535 patients that evaluates the safety and efficacy of losmapimod (GW856553), a potent oral p38MAPK inhibitor, vs placebo in patients with non-ST-segment elevation myocardial infarction expected to undergo an invasive strategy. The coprimary end points are reduction in high-sensitivity C-reactive protein at 12 weeks and reduction in infarct size as assessed by troponin area under the curve at 72 hours. A key secondary end point is 72-hour and 12-week B-type natriuretic peptide levels as a measure of cardiac remodeling and ventricular strain. The primary safety assessments are serious and nonserious adverse events, results of liver function testing, and major adverse cardiac events. Cardiac magnetic resonance imaging (N = 117) and coronary flow reserve (N = 13) substudies will assess the effects of losmapimod on infarct size, myocardial function, and coronary vasoregulation. Information gained from the SOLSTICE trial will inform further testing of this agent in larger clinical trials.
    American heart journal 11/2012; 164(5):646-653.e3. · 4.65 Impact Factor
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    ABSTRACT: This study sought to determine the effects of a p38 mitogen-activated protein kinase inhibitor, losmapimod, on vascular inflammation, by (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography imaging. The p38 mitogen-activated protein kinase cascade plays an important role in the initiation and progression of inflammatory diseases, including atherosclerosis. Patients with atherosclerosis on stable statin therapy (n = 99) were randomized to receive losmapimod 7.5 mg once daily (lower dose [LD]), twice daily (higher dose [HD]) or placebo for 84 days. Vascular inflammation was assessed by FDG positron emission tomography/computed tomography imaging of the carotid arteries and aorta; analyses focused on the index vessel (the artery with the highest average maximum tissue-to-background ratio [TBR] at baseline). Serum inflammatory biomarkers and FDG uptake in visceral and subcutaneous fat were also measured. The primary endpoint, change from baseline in average TBR across all segments in the index vessel, was not significantly different between HD and placebo (ΔTBR: -0.04 [95% confidence interval [CI]: -0.14 to +0.06], p = 0.452) or LD and placebo (ΔTBR: -0.02 [95% CI: -0.11 to +0.06], p = 0.579). However, there was a statistically significant reduction in average TBR in active segments (TBR ≥1.6) (HD vs. placebo: ΔTBR: -0.10 [95% CI: -0.19 to -0.02], p = 0.0125; LD vs. placebo: ΔTBR: -0.10 [95% CI: -0.18 to -0.02], p = 0.0194). The probability of a segment being active was also significantly reduced for HD when compared with placebo (OR: 0.57 [95% CI: 0.41 to 0.81], p = 0.002). Within the HD group, reductions were observed in placebo-corrected inflammatory biomarkers including high-sensitivity C-reactive protein (% reduction: -28% [95% CI: -46 to -5], p = 0.023) as well as FDG uptake in visceral fat (ΔSUV: -0.05 [95% CI: -0.09 to -0.01], p = 0.018), but not subcutaneous fat. Despite nonsignificant changes for the primary endpoint of average vessel TBR, HD losmapimod reduced vascular inflammation in the most inflamed regions, concurrent with a reduction in inflammatory biomarkers and FDG uptake in visceral fat. These results suggest a systemic anti-inflammatory effect. (A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging; NCT00633022).
    JACC. Cardiovascular imaging 09/2012; 5(9):911-22. · 14.29 Impact Factor
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    ABSTRACT: Oxidized low-density lipoprotein reduces endothelial nitric oxide production (an important mediator of vasoregulation) and activates p38 mitogen-activated protein kinase (MAPK), a mediator of vascular inflammation. Animal models of vascular stress have previously predicted improvements in vascular function after p38 MAPK inhibition. We hypothesized that a selective p38α/β MAPK inhibitor (losmapimod; GW856553) would improve compromised nitric oxide-mediated vasoregulation in patients with hypercholesterolemia. Untreated hypercholesterolemic patients (low-density lipoprotein cholesterol >4.1 mmol/L) were randomized to receive losmapimod 7.5 mg (n=27) or placebo (n=29) twice daily for 28 days. Patients with known vascular disorders (eg, diabetes mellitus, coronary heart disease) were excluded. Forearm blood flow was measured by venous occlusion plethysmography in response to serial intra-arterial infusion of acetylcholine, sodium nitroprusside, and N(G)-monomethyl-L-arginine (L-NMMA). Acetylcholine and L-NMMA responses were significantly impaired (P=0.01 and P=0.03) compared with responses in control subjects (n=12). In hypercholesterolemic patients treated with losmapimod, responses to acetylcholine were improved by 25% (95% confidence interval, 5 to 48; P=0.01), to sodium nitroprusside by 20% (95% confidence interval, 3 to 40; P=0.02), and to L-NMMA by 10% (95% confidence interval, -1 to 23; P=0.07) compared with placebo. C-reactive protein was reduced by 57% (95% confidence interval, -81 to -6%; P<0.05) in patients treated with losmapimod compared with placebo. Losmapimod improves nitric oxide-mediated vasodilatation in hypercholesterolemic patients, which is consistent with findings in previous translational animal models. These data support the hypothesis that attenuating the inflammatory milieu by inhibiting p38 MAPK activity improves NO activity. This suggests p38 MAPK as a novel target for patients with cardiovascular disease.
    Circulation 02/2011; 123(5):515-23. · 15.20 Impact Factor
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    ABSTRACT: To evaluate whether a p38α/β mitogen-activated protein kinase inhibitor, SB-681323, would limit the elevation of an inflammatory marker, high-sensitivity C-reactive protein (hsCRP), after a percutaneous coronary intervention (PCI). Coronary artery stents provide benefit by maintaining lumen patency but may incur vascular trauma and inflammation, leading to myocardial damage. A key mediator for such stress signaling is p38 mitogen-activated protein kinase. Patients with angiographically documented coronary artery disease receiving stable statin therapy and about to undergo PCI were randomly selected to receive SB-681323, 7.5 mg (n=46), or placebo (n=46) daily for 28 days, starting 3 days before PCI. On day 3, before PCI, hsCRP was decreased in the SB-681323 group relative to the placebo group (29% lower; P=0.02). After PCI, there was a statistically significant attenuation in the increase in hsCRP in the SB-681323 group relative to the placebo group (37% lower on day 5 [P=0.04]; and 40% lower on day 28 [P=0.003]). There were no adverse safety signals after 28 days of treatment with SB-681323. In the setting of statin therapy, SB-681323 significantly attenuated the post-PCI inflammatory response, as measured by hsCRP. This inflammatory dampening implicates p38 mitogen-activated protein kinase in the poststent response, potentially defining an avenue to limit poststent restenosis.
    Arteriosclerosis Thrombosis and Vascular Biology 11/2010; 30(11):2256-63. · 6.34 Impact Factor
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    ABSTRACT: The relationship between specific gene regulation and subsequent development and progression of atherosclerosis is incompletely understood. We hypothesized that genes in the vasculature related to cholesterol metabolism, inflammation, and insulin signaling pathways are differentially regulated in a site-specific and time-dependent manner. Expression of 59 genes obtained from coronary, carotid, and thoracic aortic arteries were characterized from diabetic (DM)/hypercholesterolemic (HC) swine (n=52) 1, 3, and 6 months after induction. Lesion development in the 3 arterial beds was quantified and characterized at 1, 3, 6, and 9 months. Progressive lesion development was observed in the coronary>thoracic aorta>carotid arteries. Genes involved in cholesterol metabolism and insulin pathways were upregulated in coronaries>thoracic aortae>carotids. Inflammatory genes were more markedly upregulated in coronary arteries than the other 2 arteries. Genes implicated in plaque instability (eg, matrix metalloproteinase-9, CCL2 and Lp-PLA(2) mRNAs) were only upregulated at 6 months in coronary arteries. Variable gene expression, both in regard to the arterial bed and duration of disease, was associated with variable plaque development and progression. These findings may provide further insight into the atherosclerotic process and development of potential therapeutic targets.
    Arteriosclerosis Thrombosis and Vascular Biology 06/2008; 28(5):850-5. · 6.34 Impact Factor
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    ABSTRACT: Peroxisome proliferator-activated receptor (PPAR)-delta is a transcription factor that belongs to the PPAR family. PPAR-delta is abundantly expressed in the heart, and its role in the heart is largely unknown. We tested whether pharmacological activation of PPAR-delta protects the heart from ischemia/reperfusion (I/R) injury in male Zucker fatty rats, a rodent model of obesity and dyslipidemia. A highly selective PPAR-delta agonist, [4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl] thio]-2-methylphenoxy]acetic acid (GW0742), was administered for 7 days at 10 mg/kg/day (p.o., once a day). Ischemic injury was produced by occlusion of the left anterior descending artery for 30 min followed by reperfusion for up to 24 h. Treatment with GW0742 reduced serum levels of cardiac troponin-I and infarct size by 63% (p < 0.01) and 32% (p < 0.01), respectively, and improved left ventricular function. Treatment with GW0742 up-regulated gene expression involved in cardiac fatty acid oxidation, increased fat use in the heart, and reduced serum levels of free fatty acids. The enhanced cardiac expression of interleukin (IL)-6, IL-8, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 induced by I/R were significantly attenuated by GW0742. Treatment with GW0742 also reduced apoptotic cardiomyocytes by 34% and cardiac caspase-3 activity by 61% (both p < 0.01 versus vehicle). GW0742 differentially regulated Bcl family members, favoring cell survival, and attenuated I/R-induced cardiac mitochondrial damage. In addition, GW0742 treatment augmented the cardiac Akt signaling pathway, as reflected by enhanced phospho-3-phosphoinositide-dependent kinase-1 and p-Akt. The results indicate that activation of PPAR-delta protected the heart from I/R injury in Zucker fatty rats, and multiple mechanisms including amelioration of lipotoxicity, anti-inflammation, and up-regulation of prosurvival signaling contribute together to the cardioprotection.
    Journal of Pharmacology and Experimental Therapeutics 06/2008; 325(2):466-74. · 3.89 Impact Factor
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    ABSTRACT: Previously, it was shown that selective deletion of peroxisome proliferator activated receptor delta (PPARdelta) in the heart resulted in a cardiac lipotoxicity, hypertrophy, and heart failure. The aim of the present study was to determine the effects of chronic and selective pharmacological activation of PPARdelta in a model of congestive heart failure. PPARdelta-specific agonist treatment (GW610742X at 30 and 100 mg/kg/day for 6-9 weeks) was initiated immediately postmyocardial infarction (MI) in Sprague-Dawley rats. Magnetic resonance imaging/spectroscopy was used to assess cardiac function and energetics. A 1-(13)C glucose clamp was performed to assess relative cardiac carbohydrate versus fat oxidation. Additionally, cardiac hemodynamics and reverse-transcription polymerase chain reaction gene expression analysis was performed. MI rats had significantly reduced left ventricle (LV) ejection fractions and whole heart phosphocreatine/adenosine triphosphate ratio compared with Sham animals (reduction of 43% and 14%, respectively). However, GW610742X treatment had no effect on either parameter. In contrast, the decrease in relative fat oxidation rate observed in both LV and right ventricle (RV) following MI (decrease of 58% and 54%, respectively) was normalized in a dose-dependent manner following treatment with GW610742X. These metabolic changes were associated with an increase in lipid transport/metabolism target gene expression (eg, CD36, CPT1, UCP3). Although there was no difference between groups in LV weight or infarct size measured upon necropsy, there was a dramatic reduction in RV hypertrophy and lung congestion (decrease of 22-48%, P<0.01) with treatment which was associated with a >7-fold decrease (P<0.05) in aterial natriuretic peptide gene expression in RV. Diuretic effects were not observed with GW610742X. In conclusion, chronic treatment with a selective PPARdelta agonist normalizes cardiac substrate metabolism and reduces RV hypertrophy and pulmonary congestion consistent with improvement in congestive heart failure.
    Journal of Cardiovascular Pharmacology 07/2007; 50(1):25-34. · 2.38 Impact Factor
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    ABSTRACT: Reduced plasma concentrations of high-density lipoprotein-cholesterol (HDL-C) are a significant risk factor for cardiovascular disease. Mechanisms that regulate HDL-C concentrations represent an important area of investigation. Comparative transcriptome analyses of monocyte-derived macrophages (MDM) from a large population of low HDL-C subjects and age- and sex-matched controls revealed a cluster of inflammatory genes highly expressed in low HDL-C subjects. The expression levels of peroxisome proliferator activated receptor (PPAR) gamma and several antioxidant metallothionein genes were decreased in MDM from all low HDL-C groups compared with controls, as was the expression of other genes regulated by PPARgamma, including CD36, adipocyte fatty acid binding protein (FABP4), and adipophilin (ADFP). In contrast, PPARdelta expression was increased in MDM from low HDL-C groups. Quantitative RT-PCR corroborated all major findings from the microarray analysis in two separate patient cohorts. Expression of several inflammatory cytokine genes including interleukin 1beta, interleukin 8, and tumor necrosis factor alpha were highly increased in low HDL-C subjects. The activated proinflammatory state of monocytes and MDM in low HDL-C subjects constitutes a novel parameter of risk associated with HDL deficiency, related to altered expression of metallothionein genes and the reciprocal regulation of PPARgamma and PPARdelta.
    Arteriosclerosis Thrombosis and Vascular Biology 06/2007; 27(5):1115-22. · 6.34 Impact Factor
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    ABSTRACT: To identify genes involved in the regulation of plasma high density lipoprotein (HDL) cholesterol (HDL-C) levels, patients with low HDL-C and age- and sex-matched controls (normal HDL-C) were extensively characterized. Comparative transcriptome analysis was carried out in cholesterol-loaded monocyte-derived macrophages from low HDL subjects segregated into groups with or without cholesterol efflux defects or ABCA1 mutations. Clusters of differentially regulated genes were evident in the low HDL groups as compared with controls. Of particular note, expression of cathepsin D (CTSD), a lysosomal proteinase, was reduced by approximately 50% in monocyte-derived macrophages of low HDL-C subjects, most significantly those with cholesterol efflux defects but without mutations in ABCA1 (p < 0.01). These results were verified by reverse transcription-PCR and replicated in a second cohort. We show here that blocking the activity or expression of CTSD, by pepstatin or CTSD small interfering RNA, respectively, reduced ABCA1 expression and protein abundance in both macrophages and CHO cells and apolipoprotein A-I-mediated lipid efflux by more than 70%. Conversely, expression of CTSD increased both ABCA1 mRNA expression and cellular ABCA1 protein. Consistent with its role in the proteolytic processing of prosaposin, inactivation of CTSD function resulted in the accumulation of glycosphingo-lipid and free cholesterol in late endosomes/lysosomes, a phenotype similar to NPC1 deficiency. Inhibition of CTSD also caused retention of ABCA1 in lysosomal compartments, reducing its trafficking to the plasma membrane. These studies demonstrate a novel and potentially important role for CTSD in intracellular cholesterol trafficking and ABCA1-mediated efflux. Therefore, decreased CTSD expression may contribute to low plasma HDL-C levels.
    Journal of Biological Chemistry 01/2007; 281(52):39971-81. · 4.65 Impact Factor
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    ABSTRACT: Substituted 3-(phenylamino)-1H-pyrrole-2,5-diones were identified from a high throughput screen as inducers of human ATP binding cassette transporter A1 expression. Mechanism of action studies led to the identification of GSK3987 as an LXR ligand. GSK3987 recruits the steroid receptor coactivator-1 to human LXRalpha and LXRbeta with EC(50)s of 40 nM, profiles as an LXR agonist in functional assays, and activates LXR though a mechanism that is similar to first generation LXR agonists.
    Journal of Medicinal Chemistry 09/2005; 48(17):5419-22. · 5.61 Impact Factor
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    ABSTRACT: Historically, the G protein-coupled receptor (GPCR) protein family has proven to be an extremely tractable target class (1). It is estimated that approximately one-half of all drugs currently marketed exert their actions, either directly or indirectly, via GPCRs (2). Given the potential commercial opportunities emanating from the identification of small molecule modulators of “novel” GPCRs (currently, GPCRs generate in excess of $25 billion per year in worldwide sales revenue [3]), it is not surprising that it is with great enthusiasm that both the pharmaceutical industry and academia move toward identifying novel members of this protein class.
    Methods in molecular biology (Clifton, N.J.) 02/2005; 306:27-49. · 1.29 Impact Factor
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    ABSTRACT: Urotensin-II (U-II), the most potent mammalian vasoconstrictor identified, and its receptor, UT, exhibits increased expression in cardiac tissue and plasma in congestive heart failure (CHF) patients. Cardiomyocyte hypertrophy is primarily responsible for increased myocardial mass associated with cardiac injury. Neurohumoral factors such as angiotensin-II, endothelin-1, catecholamines, and inflammatory cytokines are thought to mediate this response. U-II shares similar biological activities with other hypertrophic G(q)-coupled receptor ligands such as angiotensin-II and endothelin-1, but a role for U-II in cardiomyocyte hypertrophy has not been characterized. The hypothesis of the current study was that U-II, acting through its G(q)-coupled receptor UT plays a hypertrophic role in cardiac hypertrophic remodeling. We report that adenoviral upregulation of the UT receptor "unmasked" U-II-induced hypertrophy in H9c2 cardiomyocytes, with a threshold response of 202+/-8 binding sites/cell. U-II was equally as efficacious as phenylephrine in inducing hypertrophy, measured by a reporter assay (EC(50) 0.7+/-0.2 nM) and [(3)H]-leucine incorporation (EC(50) 150+/-40 nM). A competitive peptidic UT receptor antagonist, BIM-23127, inhibited U-II-induced hypertrophy ( K(B) 34+/-6 nM). U-II did not affect cell proliferation or apoptosis, indicating that U-II is more hypertrophic than apoptotic or hyperplastic in cardiomyocytes. U-II (10 nM) stimulated interleukin-6 release in UT-expressing cardiomyocytes (4.6-fold at 6 h). Finally, in a rat heart failure model, cardiac ventricular mRNA expression of U-II, UT receptor, interleukin-6, and interleukin-1-beta is increased time-dependently following myocardial injury. These results indicate that U-II might play a role in cardiac remodeling associated with CHF by stimulation of cardiomyocyte hypertrophy via UT, and through upregulation of inflammatory cytokines. As such, UT antagonism may represent a novel therapeutic target for the clinical management of heart failure.
    Archiv für Experimentelle Pathologie und Pharmakologie 11/2004; 370(4):238-50. · 2.15 Impact Factor
  • ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY; 01/2004
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    ABSTRACT: Inflammatory mediators that originate in vascular and extravascular tissues promote coronary lesion formation. Adipose tissue may function as an endocrine organ that contributes to an inflammatory burden in patients at risk of cardiovascular complications. In this study, we sought to compare expression of inflammatory mediators in epicardial and subcutaneous adipose stores in patients with critical CAD. Paired samples of epicardial and subcutaneous adipose tissues were harvested at the outset of elective CABG surgery (n=42; age 65+/-10 years). Local expression of chemokine (monocyte chemotactic protein [MCP]-1) and inflammatory cytokines (interleukin [IL]-1beta, IL-6, and tumor necrosis factor [TNF]-alpha) was analyzed by TaqMan real-time reverse transcription-polymerase chain reaction (mRNA) and by ELISA (protein release over 3 hours). Significantly higher levels of IL-1beta, IL-6, MCP-1, and TNF-alpha mRNA and protein were observed in epicardial adipose stores. Proinflammatory properties of epicardial adipose tissue were noted irrespective of clinical variables (diabetes, body mass index, and chronic use of statins or ACE inhibitors/angiotensin II receptor blockers) or plasma concentrations of circulating biomarkers. In a subset of samples (n=11), global gene expression was explored by DNA microarray hybridization and confirmed the presence of a broad inflammatory reaction in epicardial adipose tissue in patients with coronary artery disease. The above findings were paralleled by the presence of inflammatory cell infiltrates in epicardial adipose stores. Epicardial adipose tissue is a source of several inflammatory mediators in high-risk cardiac patients. Plasma inflammatory biomarkers may not adequately reflect local tissue inflammation. Current therapies do not appear to eliminate local inflammatory signals in epicardial adipose tissue.
    Circulation 12/2003; 108(20):2460-6. · 15.20 Impact Factor