circulation Volume 117, Issue 13; April 1, 2008
[摘要1]
Differential Behaviors of Atrial Versus Ventricular Fibroblasts: A Potential Role for Platelet-Derived Growth Factor in Atrial-Ventricular Remodeling Differences
Brett Burstein, Eric Libby, Angelino Calderone, and Stanley Nattel
Circulation. 2008;117:1630-1641; published online before print March 17 2008, doi:10.1161/CIRCULATIONAHA.107.748053
Background— In various heart disease paradigms, atria show stronger fibrotic responses than ventricles. The possibility that atrial and ventricular fibroblasts respond differentially to pathological stimuli has not been examined.
Methods and Results— We compared various morphological, secretory, and proliferative response indexes of canine atrial versus ventricular fibroblasts. Cultured atrial fibroblasts showed faster cell surface area increases, distinct morphology at confluence, and greater -smooth muscle actin expression than ventricular fibroblasts. Atrial fibroblast proliferation ([3H]thymidine incorporation) responses were consistently greater for a range of growth factors, including fetal bovine serum, platelet-derived growth factor (PDGF), basic fibroblast growth factor, angiotensin II, endothelin-1, and transforming growth factor-β1. Normal atrial tissue showed larger myofibroblast density compared with ventricular tissue, and the difference was exaggerated by congestive heart failure. Congestive heart failure atria showed larger fractions of fibroblasts in mitotic phases compared with ventricles and displayed enhanced gene expression of fibroblast-selective markers (collagen-1, collagen-3, fibronectin-1). Gene microarrays revealed 225 differentially expressed transcript probe sets between paired atrial and ventricular fibroblast samples, including extracellular matrix (eg, fibronectin, laminin, fibulin), cell signaling (PDGF, PDGF receptor, angiopoietin, vascular endothelial growth factor), structure (keratin), and metabolism (xanthine dehydrogenase) genes, identifying PDGF as a candidate contributor to atrial-ventricular fibroblast differences. PDGF receptor gene expression was greater in normal atrium compared with ventricle, and congestive heart failure differentially enhanced atrial versus ventricular PDGF and PDGF receptor gene expression. PDGF receptor protein expression and -smooth muscle actin protein expression were enhanced in isolated congestive heart failure fibroblasts. The PDGF receptor tyrosine kinase inhibitor AG1295 eliminated fetal bovine serum– and transforming growth factor-β1–stimulated atrial-ventricular fibroblast proliferative response differences.
Conclusions— Atrial fibroblasts behave differently than ventricular fibroblasts over a range of in vitro and in vivo paradigms, with atrial fibroblasts showing enhanced reactivity that may explain greater atrial fibrotic responses. PDGF signaling is particularly important for atrium-selective fibroblast responses and may represent a novel target for arrhythmogenic atrial structural remodeling prevention.
[摘要2]
Fractalkine Deficiency Markedly Reduces Macrophage Accumulation and Atherosclerotic Lesion Formation in CCR2–/– Mice: Evidence for Independent Chemokine Functions in Atherogenesis
Noah Saederup, Liana Chan, Sergio A. Lira, and Israel F. Charo
Circulation. 2008;117:1642-1648; published online before print December 28 2007, doi:10.1161/CIRCULATIONAHA.107.743872
Background— Monocyte-derived foam cells are the hallmark of early atherosclerosis, and recent evidence indicates that chemokines play important roles in directing monocyte migration from the blood to the vessel wall. Genetic deletions of monocyte chemoattractant protein-1 (MCP-1, CCL2), fractalkine (CX3CL1), or their cognate receptors, CCR2 and CX3CR1, markedly reduce atherosclerotic lesion size in murine models of atherosclerosis. The aim of this study was to determine whether these 2 chemokines act independently or redundantly in promoting atherogenesis.
Methods and Results— We crossed CX3CL1–/–ApoE–/– and CCR2–/–ApoE–/– mice to create CX3CL1–/–CCR2–/–ApoE–/– triple knockouts and performed a 4-arm atherosclerosis study. Here, we report that deletion of CX3CL1 in CCR2–/– mice dramatically reduced macrophage accumulation in the artery wall and the subsequent development of atherosclerosis. Deletion of CX3CL1 did not reduce the number of circulating monocytes in either "wild-type" ApoE–/– mice or CCR2–/–ApoE–/– mice, which suggests a role for CX3CL1 in the direct recruitment and/or capture of CCR2-deficient monocytes.
Conclusions— These data provide the first in vivo evidence for independent roles for CCR2 and CX3CL1 in macrophage accumulation and atherosclerotic lesion formation and suggest that successful therapeutic strategies may need to target multiple chemokines or chemokine receptors.
[摘要3]
Combined Inhibition of CCL2, CX3CR1, and CCR5 Abrogates Ly6Chi and Ly6Clo Monocytosis and Almost Abolishes Atherosclerosis in Hypercholesterolemic Mice
Christophe Combadière, Stéphane Potteaux, Mathieu Rodero, Tabassome Simon, Adeline Pezard, Bruno Esposito, Régine Merval, Amanda Proudfoot, Alain Tedgui, and Ziad Mallat
Circulation. 2008;117:1649-1657; published online before print March 17 2008, doi:10.1161/CIRCULATIONAHA.107.745091
Background— Monocytes are critical mediators of atherogenesis. Deletion of individual chemokines or chemokine receptors leads to significant but only partial inhibition of lesion development, whereas deficiency in other signals such as CXCL16 or CCR1 accelerates atherosclerosis. Evidence that particular chemokine pathways may cooperate to promote monocyte accumulation into inflamed tissues, particularly atherosclerotic arteries, is still lacking.
Methods and Results— Here, we show that chemokine-mediated signals critically determine the frequency of monocytes in the blood and bone marrow under both noninflammatory and atherosclerotic conditions. Particularly, CCL2-, CX3CR1-, and CCR5-dependent signals differentially alter CD11b+ Ly6G– 7/4hi (also known as Ly6Chi) and CD11b+ Ly6G– 7/4lo (Ly6Clo) monocytosis. Combined inhibition of CCL2, CX3CR1, and CCR5 in hypercholesterolemic, atherosclerosis-susceptible apolipoprotein E–deficient mice leads to abrogation of bone marrow monocytosis and to additive reduction in circulating monocytes despite persistent hypercholesterolemia. These effects are associated with a marked and additive 90% reduction in atherosclerosis. Interestingly, lesion size highly correlates with the number of circulating monocytes, particularly the CD11b+ Ly6G– 7/4lo subset.
Conclusions— CCL2, CX3CR1, and CCR5 play independent and additive roles in atherogenesis. Signals mediated through these pathways critically determine the frequency of circulating monocyte subsets and thereby account for almost all macrophage accumulation into atherosclerotic arteries.
[摘要4]
Abdominal Obesity and the Risk of All-Cause, Cardiovascular, and Cancer Mortality: Sixteen Years of Follow-Up in US Women
Cuilin Zhang, Kathryn M. Rexrode, Rob M. van Dam, Tricia Y. Li, and Frank B. Hu
Circulation. 2008;117:1658-1667; published online before print March 24 2008, doi:10.1161/CIRCULATIONAHA.107.739714
Background— Accumulating evidence indicates that abdominal adiposity is positively related to cardiovascular disease (CVD) risk and some other diseases independently of overall adiposity. However, the association of premature death resulting from these diseases with abdominal adiposity has not been widely studied, and findings are inconsistent.
Methods and Results— In a prospective cohort study of 44 636 women in the Nurses’ Health Study, associations of abdominal adiposity with all-cause and cause-specific mortality were examined. During 16 years of follow-up, 3507 deaths were identified, including 751 cardiovascular deaths and 1748 cancer deaths. After adjustment for body mass index and potential confounders, the relative risks across the lowest to the highest waist circumference quintiles were 1.00, 1.11, 1.17, 1.31, and 1.79 (95% confidence interval [CI], 1.47 to 1.98) for all-cause mortality; 1.00, 1.04, 1.04, 1.28, and 1.99 (95% CI, 1.44 to 2.73) for CVD mortality; and 1.00, 1.18, 1.20, 1.34, and 1.63 (95% CI, 1.32 to 2.01) for cancer mortality (all P<0.001 for trend). Among normal-weight women (body mass index, 18.5 to <25 kg/m2), abdominal obesity was significantly associated with elevated CVD mortality: Relative risk associated with waist circumference 88 cm was 3.02 (95% CI, 1.31 to 6.99) and for waist-to-hip ratio >0.88 was 3.45 (95% CI, 2.02 to 6.92). After adjustment for waist circumference, hip circumference was significantly and inversely associated with CVD mortality.
Conclusions— Anthropometric measures of abdominal adiposity were strongly and positively associated with all-cause, CVD, and cancer mortality independently of body mass index. Elevated waist circumference was associated with significantly increased CVD mortality even among normal-weight women.
[摘要5]
Age-Dependent Associations Between Chronic Periodontitis/Edentulism and Risk of Coronary Heart Disease
Thomas Dietrich, Monik Jimenez, Elizabeth A. Krall Kaye, Pantel S. Vokonas, and Raul I. Garcia
Circulation. 2008;117:1668-1674; published online before print March 24 2008, doi:10.1161/CIRCULATIONAHA.107.711507
Background— Several epidemiological studies have suggested periodontitis as a risk factor for coronary heart disease (CHD), but results have been inconsistent.
Methods and Results— We evaluated the association between clinical and radiographic measures of periodontitis, edentulism, and incident CHD (angina, myocardial infarction, or fatal CHD) among 1203 men in the VA Normative Aging and Dental Longitudinal Studies who were followed up with triennial comprehensive medical and dental examinations up to 35 years (median 24 years). Cox proportional hazards models with time-varying effects of exposure and potential confounders were fit. We found a significant dose-dependent association between periodontitis and CHD incidence among men <60 years of age (hazard ratio 2.12, 95% confidence interval 1.26 to 3.60 comparing highest versus lowest category of radiographic bone loss, P for trend=0.02), independent of age, body mass index, smoking, alcohol intake, diabetes mellitus, fasting glucose, total cholesterol, high-density lipoprotein cholesterol, triglycerides, hypertension, systolic and diastolic blood pressure, education, marital status, income, and occupation. No association was found among men >60 years of age. Similar results were found when the sum of probing pocket depths was used as a measure of periodontitis. Among men 60 years of age, edentulous men tended to have a higher risk of CHD than dentate men in the lowest bone loss (hazard ratio 1.61, 95% confidence interval 0.95 to 2.73) and lowest pocket depth (hazard ratio 1.72, 95% confidence interval 1.03 to 2.85) categories, independent of confounders.
Conclusions— Chronic periodontitis is associated with incidence of CHD among younger men, independent of established cardiovascular risk factors.
[摘要6]
Repeated Replication and a Prospective Meta-Analysis of the Association Between Chromosome 9p21.3 and Coronary Artery Disease
Heribert Schunkert, Anika Götz, Peter Braund, Ralph McGinnis, David-Alexandre Tregouet, Massimo Mangino, Patrick Linsel-Nitschke, Francois Cambien, Christian Hengstenberg, Klaus Stark, Stefan Blankenberg, Laurence Tiret, Pierre Ducimetiere, Andrew Keniry, Mohammed J.R. Ghori, Stefan Schreiber, Nour Eddine El Mokhtari, Alistair S. Hall, Richard J. Dixon, Alison H. Goodall, Henrike Liptau, Helen Pollard, Daniel F. Schwarz, Ludwig A. Hothorn, H. -Erich Wichmann, Inke R. König, Marcus Fischer, Christa Meisinger, Willem Ouwehand, Panos Deloukas, John R. Thompson, Jeanette Erdmann, Andreas Ziegler, Nilesh J. Samani for the Cardiogenics Consortium
Circulation. 2008;117:1675-1684; published online before print March 24 2008, doi:10.1161/CIRCULATIONAHA.107.730614
Background— Recently, genome-wide association studies identified variants on chromosome 9p21.3 as affecting the risk of coronary artery disease (CAD). We investigated the association of this locus with CAD in 7 case-control studies and undertook a meta-analysis.
Methods and Results— A single-nucleotide polymorphism (SNP), rs1333049, representing the 9p21.3 locus, was genotyped in 7 case-control studies involving a total of 4645 patients with myocardial infarction or CAD and 5177 controls. The mode of inheritance was determined. In addition, in 5 of the 7 studies, we genotyped 3 additional SNPs to assess a risk-associated haplotype (ACAC). Finally, a meta-analysis of the present data and previously published samples was conducted. A limited fine mapping of the locus was performed. The risk allele (C) of the lead SNP, rs1333049, was uniformly associated with CAD in each study (P<0.05). In a pooled analysis, the odds ratio per copy of the risk allele was 1.29 (95% confidence interval, 1.22 to 1.37; P=0.0001). Haplotype analysis further suggested that this effect was not homogeneous across the haplotypic background (test for interaction, P=0.0079). An autosomal-additive mode of inheritance best explained the underlying association. The meta-analysis of the rs1333049 SNP in 12 004 cases and 28 949 controls increased the overall level of evidence for association with CAD to P=6.04x10–10 (odds ratio, 1.24; 95% confidence interval, 1.20 to 1.29). Genotyping of 31 additional SNPs in the region identified several with a highly significant association with CAD, but none had predictive information beyond that of the rs1333049 SNP.
Conclusion— This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD.
[摘要7]
N-Terminal Prohormone Brain Natriuretic Peptide as a Predictor of Cardiovascular Disease and Mortality in Blacks With Hypertensive Kidney Disease: The African American Study of Kidney Disease and Hypertension (AASK)
B.C. Astor, S. Yi, L. Hiremath, T. Corbin, V. Pogue, B. Wilkening, G. Peterson, J. Lewis, J.P. Lash, F. Van Lente, J. Gassman, X. Wang, G. Bakris, L.J. Appel, and G. Contreras
Circulation. 2008;117:1685-1692; published online before print March 24 2008, doi:10.1161/CIRCULATIONAHA.107.724187
Background— Higher levels of N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) predict cardiovascular disease (CVD) in several disease states, but few data are available in patients with chronic kidney disease or in blacks.
Methods and Results— The African American Study of Kidney Disease and Hypertension trial enrolled hypertensive blacks with a glomerular filtration rate of 20 to 65 mL · min–1 · 1.73 m–2 and no other identified cause of kidney disease. NT-proBNP was measured with a sandwich chemiluminescence immunoassay (coefficient of variation 2.9%) in 994 African American Study of Kidney Disease and Hypertension participants. NT-proBNP was categorized as undetectable, low, moderate, or high. Proteinuria was defined as 24-hour urinary protein–creatinine ratio >0.22. A total of 134 first CVD events (CVD death or hospitalization for coronary artery disease, heart failure, or stroke) occurred over a median of 4.3 years. Participants with high NT-proBNP were much more likely to have a CVD event than participants with undetectable NT-proBNP after adjustment (relative hazard 4.0 [95% confidence interval [CI] 2.1 to 7.6]). A doubling of NT-proBNP was associated with a relative hazard of 1.3 (95% CI 1.0 to 1.6) for coronary artery disease, 1.7 (95% CI 1.4 to 2.2) for heart failure, 1.1 (95% CI 0.9 to 1.4) for stroke, and 1.8 (95% CI 1.4 to 2.4) for CVD death. The association of NT-proBNP with CVD events was significantly stronger (Pinteraction=0.05) in participants with than in those without proteinuria. Higher NT-proBNP was not associated with renal disease progression.
Conclusions— These results suggest that elevated NT-proBNP levels are associated with higher CVD risk among blacks with hypertensive kidney disease. This association may be stronger in individuals with significant proteinuria.
[摘要8]
Interrelation of Coronary Calcification, Myocardial Ischemia, and Outcomes in Patients With Intermediate Likelihood of Coronary Artery Disease: A Combined Positron Emission Tomography/Computed Tomography Study
Matthew P. Schenker, Sharmila Dorbala, Eric Cho Tek Hong, Frank J. Rybicki, Rory Hachamovitch, Raymond Y. Kwong, and Marcelo F. Di Carli
Circulation. 2008;117:1693-1700; published online before print March 24 2008, doi:10.1161/CIRCULATIONAHA.107.717512
Background— Although the value of coronary artery calcium (CAC) for atherosclerosis screening is gaining acceptance, its efficacy in predicting flow-limiting coronary artery disease remains controversial, and its incremental prognostic value over myocardial perfusion is not well established.
Methods and Results— We evaluated 695 consecutive intermediate-risk patients undergoing combined rest-stress rubidium 82 positron emission tomography (PET) perfusion imaging and CAC scoring on a hybrid PET-computed tomography (CT) scanner. The frequency of abnormal scans among patients with a CAC score 400 was higher than that in patients with a CAC score of 1 to 399 (48.5% versus 21.7%, P<0.001). Multivariate logistic regression supported the concept of a threshold CAC score 400 governing this relationship (odds ratio 2.91, P<0.001); however, the frequency of ischemia among patients with no CAC was 16.0%, and its absence only afforded a negative predictive value of 84.0%. Risk-adjusted survival analysis demonstrated a stepwise increase in event rates (death and myocardial infarction) with increasing CAC scores in patients with and without ischemia on PET myocardial perfusion imaging. Among patients with normal PET myocardial perfusion imaging, the annualized event rate in patients with no CAC was lower than in those with a CAC score 1000 (2.6% versus 12.3%, respectively). Likewise, in patients with ischemia on PET myocardial perfusion imaging, the annualized event rate in those with no CAC was lower than among patients with a CAC score 1000 (8.2% versus 22.1%).
Conclusions— Although increasing CAC content is generally predictive of a higher likelihood of ischemia, its absence does not completely eliminate the possibility of flow-limiting coronary artery disease. Importantly, a stepwise increase occurs in the risk of adverse events with increasing CAC scores in patients with and without ischemia on PET myocardial perfusion imaging.
[摘要9]
Microsomal Prostaglandin E2 Synthase-1 Deletion Leads to Adverse Left Ventricular Remodeling After Myocardial Infarction
Norbert Degousee, Shafie Fazel, Denis Angoulvant, Eva Stefanski, Sven-Christian Pawelzik, Marina Korotkova, Sara Arab, Peter Liu, Thomas F. Lindsay, Sun Zhuo, Jagdish Butany, Ren-Ke Li, Laurent Audoly, Ronald Schmidt, Carlo Angioni, Gerd Geisslinger, Per-Johan Jakobsson, and Barry B. Rubin
Circulation. 2008;117:1701-1710; published online before print March 17 2008, doi:10.1161/CIRCULATIONAHA.107.749739
Background— Pharmacological inhibition of cyclooxygenase-2 increases the risk of myocardial infarction (MI) and stroke. Microsomal prostaglandin (PG) E2 synthase-1 (mPGES-1), encoded by the Ptges gene, functions downstream from cyclooxygenase-2 in the inducible PGE2 biosynthetic pathway. We caused acute MI in Ptges+/+ and Ptges–/– mice to define the role of mPGES-1 in cardiac ischemic injury.
Methods and Results— Twenty-eight days after MI, Ptges–/– mice develop more left ventricular (LV) dilation, have worse LV systolic and diastolic function, and have higher LV end-diastolic pressure than Ptges+/+ mice but have similar pulmonary wet-to-dry weight ratios, cardiac mass, infarct size, and mortality. The length-to-width ratio of individual cardiomyocytes is significantly greater in Ptges–/– than Ptges+/+ mice after MI, a finding consistent with eccentric cardiomyocyte hypertrophy in Ptges–/– mice. Expression of atrial natriuretic peptide, brain natriuretic peptide, and - and β-myosin heavy chain, markers of ventricular hypertrophy, is higher in the LV of Ptges–/– than Ptges+/+ mice after MI. Ptges+/+ mice express cyclooxygenase-2 and mPGES-1 protein in inflammatory cells adjacent to the infarct after MI but do not express these proteins in cardiomyocytes. Ptges–/– mice express cyclooxygenase-2 in inflammatory cells adjacent to the infarct and do not express mPGES-1 in any cells in the heart. Levels of PGE2 but not PGD2, thromboxane A2, PGI2, or PGF2 are higher in the infarct and LV remote from the infarct after MI in Ptges+/+ than Ptges–/– mice.
Conclusions— In Ptges+/+ mice, mPGES-1 in inflammatory cells catalyzes PGE2 biosynthesis in the LV after MI. Deletion of mPGES-1 leads to eccentric cardiac myocyte hypertrophy, LV dilation, and impaired LV contractile function after acute MI.
[摘要10]
Clinical Predictors for Fatal Pulmonary Embolism in 15 520 Patients With Venous Thromboembolism: Findings From the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry
Silvy Laporte, Patrick Mismetti, Hervé Décousus, Fernando Uresandi, Remedios Otero, Jose Luis Lobo, Manuel Monreal, and the RIETE Investigators
Circulation. 2008;117:1711-1716; published online before print March 17 2008, doi:10.1161/CIRCULATIONAHA.107.726232
Background— Clinical predictors for fatal pulmonary embolism (PE) in patients with venous thromboembolism have never been studied.
Methods and Results— Using data from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry about patients with objectively confirmed symptomatic acute venous thromboembolism, we determined independent predictive factors for fatal PE. Between March 2001 and July 2006, 15 520 consecutive patients (mean age±SD, 66.3±16.9 years; 49.7% men) with acute venous thromboembolism were included. Symptomatic deep-vein thrombosis without symptomatic PE was observed in 58.0% (n=9008) of patients, symptomatic nonmassive PE in 40.4% (n=6264), and symptomatic massive PE in 1.6% (n=248). At 3 months, the cumulative rates of overall mortality and fatal PE were 8.65% and 1.68%, respectively. On multivariable analysis, patients with symptomatic nonmassive PE at presentation exhibited a 5.42-fold higher risk of fatal PE compared with patients with deep-vein thrombosis without symptomatic PE (P<0.001). The risk of fatal PE was multiplied by 17.5 in patients presenting with a symptomatic massive PE. Other clinical factors independently associated with an increased risk of fatal PE were immobilization for neurological disease, age >75 years, and cancer.
Conclusion— PE remains a potentially fatal disease. The clinical predictors identified in the present study should be included in any clinical risk stratification scheme to optimally adapt the treatment of PE to the risk of the fatal outcome.
[摘要11]
Percutaneous and Minimally Invasive Valve Procedures: A Scientific Statement From the American Heart Association Council on Cardiovascular Surgery and Anesthesia, Council on Clinical Cardiology, Functional Genomics and Translational Biology Interdisciplinary Working Group, and Quality of Care and Outcomes Research Interdisciplinary Working Group
Todd K. Rosengart, Ted Feldman, Michael A. Borger, Thomas A. Vassiliades, Jr, A. Marc Gillinov, Katherine J. Hoercher, Alec Vahanian, Robert O. Bonow, and William O’Neill
Circulation. 2008;117:1750-1767; published online before print March 10 2008, doi:10.1161/CIRCULATIONAHA.107.188525
The incidence of valvular heart disease is expected to increase over the next several decades as a large proportion of the US demographic advances into the later decades of life. At the same time, the next several years can be anticipated to bring a broad transition of surgical therapy to minimally invasive (minithoracotomy and small port) access and the more gradual introduction of percutaneous approaches for the correction of valvular heart disease. Broad acceptance of these technologies will require careful and sometimes perplexing comparisons of the outcomes of these new technologies with existing standards of care. The validation of percutaneous techniques, in particular, will require the collaboration of cardiologists and cardiac surgeons in centers with excellent surgical and catheter experience and a commitment to trial participation. For the near term, percutaneous techniques will likely remain investigational and will be limited in use to patients considered to be high risk or to inoperable surgical candidates. Although current-generation devices and techniques require significant modification before widespread clinical use can be adopted, it must be expected that less invasive and even percutaneous valve therapies will likely have a major impact on the management of patients with valvular heart disease over the next several years.
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本帖最后由 tnp007 于 2008-4-1 22:38 编辑 ]
