Circulation 2009年12月15日
发布于 2009-12-15 · 浏览 3265 · IP 北京北京
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Abstract 1 of 9 (Circulation. 2009;120:2414-2420.)
© 2009 American Heart Association, Inc.
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Epidemiology and Prevention
Association of Circulating Cholesteryl Ester Transfer Protein Activity With Incidence of Cardiovascular Disease in the Community
Ramachandran S. Vasan, MD; Michael J. Pencina, PhD; Sander J. Robins, MD; Justin P. Zachariah, MD; Guneet Kaur, PhD; Ralph B. D'Agostino, PhD; Jose M. Ordovas, PhD
From the Framingham Heart Study, Framingham, Mass (R.S.V., M.J.P., S.J.R., R.B.D.); Department of Biostatistics, Boston University School of Public Health, Boston, Mass (M.J.P.); Department of Mathematics and Statistics, Boston University, Boston, Mass (M.J.P., G.K., R.B.D.); Preventive Medicine and Cardiology Sections, Department of Medicine, Boston University School of Medicine, Boston, Mass (R.S.V.); Department of Cardiology, Children’s Hospital Boston and Department of Pediatrics, Harvard Medical School, Boston, Mass (J.P.Z.); and Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Mass and Department of Cardiovascular Epidemiology and Population Genetics, National Center for Cardiovascular Investigation (CNIC), Madrid, Spain (J.M.O.).
Correspondence to Ramachandran S. Vasan, MD, Framingham Heart Study, 73 Mount Wayte Ave, Framingham, MA 01702-5803. E-mail vasan@bu.edu
Received April 11, 2009; accepted September 16, 2009.
Background— Plasma high-density lipoprotein cholesterol concentration is related inversely to the risk of cardiovascular disease (CVD). Inhibiting cholesteryl ester transfer protein (CETP) activity raises high-density lipoprotein cholesterol and may be cardioprotective, but an initial clinical trial with a CETP inhibitor was stopped prematurely because of increased CVD in treated patients, raising concerns about this approach. Data relating circulating CETP concentrations to CVD incidence in the community are conflicting.
Methods and Results— Plasma CETP activity was measured in 1978 Framingham Heart Study participants (mean age, 51 years; 54% women) who attended a routine examination in 1987–1990 and were free of CVD. On follow-up (mean, 15.1 years), 320 participants experienced a first CVD event (fatal or nonfatal coronary heart disease, cerebrovascular disease, peripheral vascular disease, or heart failure). In multivariable analyses adjusted for standard risk factors including high-density lipoprotein cholesterol, plasma CETP activity was related inversely to the incidence of CVD events (hazard ratio for activity, at or above the median of 0.72; 95% confidence interval, 0.57 to 0.90; P=0.004 [compared with below median]; hazard ratio per SD increment, 0.86; 95% confidence interval, 0.76 to 0.97; P=0.01). The inverse association of CETP activity with CVD incidence remained robust in time-dependent models updating standard risk factors every 4 years and was maintained in analyses of incident "hard" CVD events (myocardial infarction, stroke, or heart failure).
Conclusions— In our prospective investigation of a community-based sample, lower plasma CETP activity was associated with greater CVD risk. These observations, if confirmed, challenge the concept that CETP inhibition may lower CVD risk.
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Abstract 2 of 9 (Circulation. 2009;120:2421-2428.)
© 2009 American Heart Association, Inc.
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Epidemiology and Prevention
Glycemic Control and Cardiovascular Events in Diabetic Hemodialysis Patients
Christiane Drechsler, MD, MSc; Vera Krane, MD; Eberhard Ritz, MD; Winfried März, MD; Christoph Wanner, MD
From the University Hospital Würzburg, Department of Medicine 1, Division of Nephrology, Würzburg, Germany (C.D., V.K., C.W.); Leiden University Medical Center, Department of Clinical Epidemiology, Leiden, the Netherlands (C.D.); University Hospital Heidelberg, Department of Medicine, Division of Nephrology, Heidelberg, Germany (E.R.); Synlab Center of Laboratory Diagnostics, Heidelberg, Germany (W.M.); Medical University of Graz, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz, Austria (W.M.); and University of Heidelberg, Mannheim Institute of Public Health, Social and Preventive Medicine, Mannheim, Germany (W.M.).
Correspondence to Christiane Drechsler, MD, Department of Medicine, Division of Nephrology, University Hospital, Oberdürrbacherstrasse 6, D-97080 Würzburg, Germany. E-mail c.drechsler@gmx.net
Received February 11, 2009; accepted September 29, 2009.
Background— Patients on maintenance dialysis treatment experience an excess mortality, predominantly of sudden cardiac death. Poor glycemic control is associated with cardiovascular comorbidities in the general population. This study investigated the impact of glycemic control on cardiac and vascular outcomes in diabetic hemodialysis patients.
Methods and Results— Glycohemoglobin A1c (HbA1c) was measured in 1255 hemodialysis patients with type 2 diabetes mellitus who participated in the German Diabetes and Dialysis Study (4D Study) and were followed up for a median of 4 years. Using Cox regression analyses, we determined hazard ratios to reach prespecified, adjudicated end points according to HbA1c levels at baseline: sudden cardiac death (n=160), myocardial infarction (n=200), stroke (n=103), cardiovascular events (n=469), death caused by heart failure (n=41), and all-cause mortality (n=617). Patients had a mean age of 66±8 years (54% male) and mean HbA1c of 6.7±1.3%. Patients with an HbA1c >8% had a >2-fold higher risk of sudden death compared with those with an HbA1c 6% (hazard ratio, 2.14; 95% confidence interval, 1.33 to 3.44), persisting in multivariate models. With each 1% increase in HbA1c, the risk of sudden death rose significantly by 18%; similarly, cardiovascular events and mortality increased by 8%. There was a trend for higher risks of stroke and deaths resulting from heart failure, whereas myocardial infarction was not affected. The increased risks of both cardiovascular events and mortality were explained mainly by the impact of HbA1c on sudden death.
Conclusions— Poor glycemic control was strongly associated with sudden cardiac death in diabetic hemodialysis patients, which accounted for increased cardiovascular events and mortality. In contrast, myocardial infarction was not affected. Whether interventions achieving tight glycemic control decrease sudden death requires further evaluation.
Clinical Trial Registration— URL: http://www.clinicalstudyresults.org. Unique identifier: CT-981–423–239.
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Abstract 3 of 9 (Circulation. 2009;120:2429-2437.)
© 2009 American Heart Association, Inc.
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Epidemiology and Prevention
Differential Clinical Outcomes Associated With Hypoglycemia and Hyperglycemia in Acute Myocardial Infarction
Abhinav Goyal, MD, MHS; Shamir R. Mehta, MD, MSc; Rafael Díaz, MD; Hertzel C. Gerstein, MD, MSc; Rizwan Afzal, MSc; Denis Xavier, MD; Lisheng Liu, MD; Prem Pais, MD; Salim Yusuf, MBBS, DPhil
From the Population Health Research Institute (A.G., S.R.M., H.C.G., R.A., S.Y.), Hamilton Health Sciences, Hamilton, Ontario, Canada; Emory Schools of Public Health and Medicine (A.G.), Atlanta, Ga; Department of Medicine (S.R.M., H.C.G., S.Y.), McMaster University, Hamilton, Ontario, Canada; Estudios Cardiologicos Latinoamerica (R.D.), Rosario, Argentina; St John’s Medical College (D.X., P.P.), Bangalore, India; Cardiovascular Institute and Fu Wai Hospital (L.L.), Chinese Hypertension League Institute, Beijing, China.
Reprint requests to Abhinav Goyal, MD, MHS, 1518 Clifton Rd NE, Room 456, Atlanta, GA 30322. E-mail agoyal4@emory.edu
Received November 21, 2008; accepted October 2, 2009.
Background— In patients with acute myocardial infarction (AMI), hyperglycemia predicts death, but the prognostic significance of hypoglycemia is controversial.
Methods and Results— We evaluated the prognostic significance of hypoglycemia and hyperglycemia in 30 536 AMI patients in a post hoc analysis of 2 large trials of glucose-insulin-potassium therapy in AMI. Glucose levels on admission and at 6 and 24 hours after admission, as well as 30-day mortality, were documented. In separate multivariable Cox models for admission and postadmission glucose, we compared the prognostic value of hypoglycemia (70 mg/dL) and hyperglycemia (140 mg/dL) with normoglycemia (>70 and <140 mg/dL). Analyses were repeated with hypoglycemia defined as glucose 60 mg/dL and in key subgroups based on diabetes or insulin (glucose-insulin-potassium) allocation status. Both high and low percentiles of admission glucose predicted increased 30-day mortality. However, for postadmission glucose, this U-shaped relationship was attenuated so that only high and not low glucose levels remained prognostic. Hyperglycemia (140 mg/dL), both on admission (adjusted hazard ratio 1.43, 95% confidence interval 1.32 to 1.56, P<0.0001) and after admission (adjusted hazard ratio 1.47, 95% confidence interval 1.31 to 1.66, P<0.0001), predicted death compared with normoglycemia. In contrast, hypoglycemia (glucose 70 mg/dL) on admission was not prognostic (adjusted hazard ratio 1.16, 95% confidence interval 0.84 to 1.62, P=0.37), nor was postadmission hypoglycemia (adjusted hazard ratio 0.96, 95% confidence interval 0.72 to 1.26, P=0.75). Exploratory analyses that redefined hypoglycemia as glucose 60 mg/dL showed consistent results, as did analyses restricted to diabetic patients (18% of the study population). Postadmission hypoglycemia was more common in insulin (glucose-insulin-potassium)–treated patients (6.9%) than in untreated patients (3.4%) but did not predict mortality in either subgroup.
Conclusions— Both admission and postadmission hyperglycemia predict 30-day death in AMI patients. In contrast, only hypoglycemia on admission predicted death, and this relationship dissipated after admission. These data suggest hypoglycemia may not be a direct mediator of adverse outcomes in AMI patients.
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Abstract 4 of 9 (Circulation. 2009;120:2438-2447.)
© 2009 American Heart Association, Inc.
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Exercise Physiology
Physical Exercise Prevents Cellular Senescence in Circulating Leukocytes and in the Vessel Wall
Christian Werner, MD; Tobias Fürster, MD; Thomas Widmann, MD; Janine Pöss, MD; Cristiana Roggia, MD; Milad Hanhoun, MD; Jürgen Scharhag, MD; Nicole Büchner, DBBSc; Tim Meyer, MD; Wilfried Kindermann, MD; Judith Haendeler, PhD; Michael Böhm, MD; Ulrich Laufs, MD
From the Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin (C.W., T.F., J.P., M.H., M.B., U.L.), Klinik für Innere Medizin I, Onkologie, Hämatologie, Klinische Immunologie und Rheumatologie (T.W.), and Institut für Pathologie (C.R.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Institut für Sport und Präventivmedizin, Universität des Saarlandes, Saarbrücken (J.S., T.M., W.K.); and Institut für Umweltmedizinische Forschung at the Universität Düsseldorf gGmbH, Düsseldorf (N.B., J.H.), Germany.
Correspondence to Ulrich Laufs, MD, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66421 Homburg/Saar, Germany. E-mail ulrich@laufs.com
Received March 1, 2009; accepted October 9, 2009.
Background— The underlying molecular mechanisms of the vasculoprotective effects of physical exercise are incompletely understood. Telomere erosion is a central component of aging, and telomere-associated proteins regulate cellular senescence and survival. This study examines the effects of exercising on vascular telomere biology and endothelial apoptosis in mice and the effects of long-term endurance training on telomere biology in humans.
Methods and Results— C57/Bl6 mice were randomized to voluntary running or no running wheel conditions for 3 weeks. Exercise upregulated telomerase activity in the thoracic aorta and in circulating mononuclear cells compared with sedentary controls, increased vascular expression of telomere repeat-binding factor 2 and Ku70, and reduced the expression of vascular apoptosis regulators such as cell-cycle–checkpoint kinase 2, p16, and p53. Mice preconditioned by voluntary running exhibited a marked reduction in lipopolysaccharide-induced aortic endothelial apoptosis. Transgenic mouse studies showed that endothelial nitric oxide synthase and telomerase reverse transcriptase synergize to confer endothelial stress resistance after physical activity. To test the significance of these data in humans, telomere biology in circulating leukocytes of young and middle-aged track and field athletes was analyzed. Peripheral blood leukocytes isolated from endurance athletes showed increased telomerase activity, expression of telomere-stabilizing proteins, and downregulation of cell-cycle inhibitors compared with untrained individuals. Long-term endurance training was associated with reduced leukocyte telomere erosion compared with untrained controls.
Conclusions— Physical activity regulates telomere-stabilizing proteins in mice and in humans and thereby protects from stress-induced vascular apoptosis.
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Abstract 5 of 9 (Circulation. 2009;120:2448-2454.)
© 2009 American Heart Association, Inc.
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Genetics
Integrative Predictive Model of Coronary Artery Calcification in Atherosclerosis
Michael McGeachie, PhD; Rachel L. Badovinac Ramoni, DMD, ScD; Josyf C. Mychaleckyj, MA, DPhil; Karen L. Furie, MD, MPH; Jonathan M. Dreyfuss, MS; Yongmei Liu, PhD; David Herrington, MD, MHS; Xiuqing Guo, PhD; João A. Lima, MD; Wendy Post, MD, MS; Jerome I. Rotter, MD; Stephen Rich, PhD; Michèle Sale, PhD; Marco F. Ramoni, PhD
From the Children’s Hospital Informatics Program (M.M., J.M.D., M.F.R.), Harvard-MIT Division of Health Sciences and Technology, Boston, Mass; Harvard Partners Center for Genetics and Genomics (M.M., M.F.R.), Harvard Medical School, Boston, Mass; Department of Developmental Biology (R.L.B.R.), Harvard School of Dental Medicine, Boston, Mass; Center for Public Health Genomics (J.C.M., S.R., M.S.) and Department of Public Health Sciences (J.C.M., S.R.), University of Virginia, Charlottesville, Va; Department of Neurology (K.L.F.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass; Department of Epidemiology and Prevention (Y.L.) and Department of Internal Medicine (D.H.), Wake Forest University School of Medicine, Winston-Salem, NC; Medical Genetics Institute (X.G., J.I.R.), Cedars Sinai, Los Angeles, Calif; Donald W. Reynolds Cardiovascular Clinical Research Center (J.A.L., W.P.), Division of Cardiology, Johns Hopkins University, Baltimore, Md; and Department of Medicine (S.R., M.S.) and Department of Biochemistry and Molecular Genetics (M.S.), University of Virginia, Charlottesville, Va.
Correspondence to Marco F. Ramoni, PhD, Harvard Partners Center for Genetics and Genomics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, e-mail marco_ramoni@harvard.edu, or Michèle Sale, PhD, Center for Public Health Genomics, PO Box 800717, West Complex Room 6111, Charlottesville, VA 22908, e-mail ms5fe@virginia.edu
Received March 19, 2009; accepted September 28, 2009.
Background— Many different genetic and clinical factors have been identified as causes or contributors to atherosclerosis. We present a model of preclinical atherosclerosis based on genetic and clinical data that predicts the presence of coronary artery calcification in healthy Americans of European descent 45 to 84 years of age in the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods and Results— We assessed 712 individuals for the presence or absence of coronary artery calcification and assessed their genotypes for 2882 single-nucleotide polymorphisms. With the use of these single-nucleotide polymorphisms and relevant clinical data, a Bayesian network that predicts the presence of coronary calcification was constructed. The model contained 13 single-nucleotide polymorphisms (from genes AGTR1, ALOX15, INSR, PRKAB1, IL1R2, ESR2, KCNK1, FBLN5, PPARA, VEGFA, PON1, TDRD6, PLA2G7, and 1 ancestry informative marker) and 5 clinical variables (sex, age, weight, smoking, and diabetes mellitus) and achieved 85% predictive accuracy, as measured by area under the receiver operating characteristic curve. This is a significant (P<0.001) improvement on models that use just the single-nucleotide polymorphism data or just the clinical variables.
Conclusions— We present an investigation of joint genetic and clinical factors associated with atherosclerosis that shows predictive results for both cases, as well as enhanced performance for their combination.
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Abstract 6 of 9 (Circulation. 2009;120:2455-2461.)
© 2009 American Heart Association, Inc.
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Interventional Cardiology
Choice of Reperfusion Strategy at Hospitals With Primary Percutaneous Coronary Intervention
A National Registry of Myocardial Infarction Analysis
Reza Fazel, MD, MSc; Harlan M. Krumholz, MD, SM; Eric R. Bates, MD; William J. French, MD; Paul D. Frederick, MPH, MBA; Brahmajee K. Nallamothu, MD, MPH, for the National Registry of Myocardial Infarction (NRMI) Investigators
From the Department of Medicine, Division of Cardiology (R.F.), Emory University School of Medicine, Atlanta, Ga; Department of Medicine, Section of Cardiovascular Medicine and the Robert Wood Johnson Clinical Scholars Program, Department of Medicine, and the Section of Health Policy and Administration, School of Public Health, Yale University School of Medicine, and the Center for Outcomes Research and Evaluation, Yale–New Haven Hospital, all in New Haven, Conn (H.M.K); the Department of Internal Medicine, Division of Cardiovascular Medicine (E.R.B., B.K.N.), University of Michigan Medical School, Ann Arbor, Mich; Harbor-UCLA Medical Center (W.J.F.), Los Angeles, Calif; ICON Lifecycle Sciences Group (P.D.F.), San Francisco, Calif; and the Veterans Affairs Ann Arbor Health Services Research and Development Center of Excellence (B.K.N.), Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Mich.
Correspondence to Reza Fazel, MD, MSc, Emory University, Division of Cardiology, Bldg A, Suite 1-North, 1256 Briarcliff Rd NE, Atlanta, GA 30306. E-mail rfazel@emory.edu
Received February 25, 2009; accepted September 17, 2009.
Background— Many hospitals with percutaneous coronary intervention (PCI) capability also use fibrinolytic therapy in patients with ST-segment elevation myocardial infarction, but factors influencing the choice of reperfusion strategy at these hospitals are poorly understood. We examined clinical and system-related factors associated with choice of reperfusion strategy in patients with ST-segment elevation myocardial infarction at PCI-capable hospitals.
Methods and Results— We analyzed patients with ST-segment elevation myocardial infarction who presented to PCI-capable hospitals between July 1, 2000, and December 31, 2006, in the National Registry of Myocardial Infarction. Hierarchical multivariable logistic regression was used to examine the association between choice of reperfusion strategy and patient-, hospital-, and system-related factors. We identified 25 579 patients who received primary PCI and 14 332 patients who received fibrinolytic therapy at 444 PCI-capable hospitals. Use of reperfusion strategies varied widely across hospitals, although primary PCI use increased over the study period. Among the key clinical factors that favored primary PCI, cardiogenic shock and delayed presentation were associated with greater use of primary PCI (adjusted odds ratios 2.14 [95% confidence interval 1.72 to 2.66] and 1.18 [95% confidence interval 1.09 to 1.27], respectively), whereas a Thrombolysis in Myocardial Infarction risk score 5 was not. In contrast, female gender, advanced age, and nonwhite race, all risk factors for intracranial hemorrhage after fibrinolytic therapy, were not associated with increased use of primary PCI. Off-hours presentation had the strongest association overall, with an 70% lower likelihood of patients undergoing primary PCI (adjusted odds ratio 0.27, 95% confidence interval 0.25 to 0.29).
Conclusions— Use of primary PCI, although increasing over recent years, is not universal at PCI-capable hospitals, and optimization of its use at such hospitals represents a potential opportunity to improve outcomes in patients with ST-segment elevation myocardial infarction.
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Abstract 7 of 9 (Circulation. 2009;120:2462-2469.)
© 2009 American Heart Association, Inc.
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Vascular Medicine
Toll-Like Receptor-2 Mediates Inflammation and Matrix Degradation in Human Atherosclerosis
Claudia Monaco, MD, PhD, FESC; Scott M. Gregan, BSc; Tina J. Navin, BSc; Brian M.J. Foxwell, PhD, DSc, FRCPath; Alun H. Davies, MA, BM, BCh, DM, FRCS, FHEA; Marc Feldmann, MB, BS, BSc, PhD, FRCPath, FRCP, F***, FAA, FRS
From the Kennedy Institute of Rheumatology (C.M., S.M.G., T.J.N., B.M.J.F., M.F.) and Surgery, Oncology, Reproductive Biology, and Anesthetic Divisions (C.M., T.J.N., A.H.D.), Faculty of Medicine, Imperial College, London, United Kingdom.
Correspondence to Dr Marc Feldmann or Dr Claudia Monaco, Kennedy Institute of Rheumatology Division, Imperial College, 65 Aspenlea Rd, London W6 8LH, UK. E-mail m.feldmann@imperial.ac.uk or c.monaco@imperial.ac.uk
Received January 22, 2009; accepted October 5, 2009.
Background— Inflammation and matrix degradation are the hallmarks of high-risk atherosclerosis that leads to myocardial infarction and stroke. Toll-like receptors (TLRs), key players in innate immunity, are upregulated in atherosclerotic lesions, but their functional role in human atherosclerosis is unknown. We explored the effects of blocking TLR-2, TLR-4, and myeloid differentiation primary response gene 88 (MyD88), a signaling adaptor shared by most TLRs and interleukin-1 receptor (IL-1R), in an in vitro model of human atherosclerosis.
Methods and Results— Carotid endarterectomies were obtained from patients with symptomatic carotid disease. Cells were isolated via enzymatic tissue dissociation and cultured in the presence or absence of TLR signaling blockers. A dominant-negative form of MyD88 (MyD88DN) decreased the production of monocyte chemotactic protein-1/CCL2 (P=0.000), IL-8/CXCL8 (P=0.006), IL-6 (P=0.002), matrix metalloproteinase-1 (MMP-1; P=0.002), and MMP-3 (P=0.000), as well as nuclear factor-B activation (P<0.05) in atheroma cell cultures. IL-1R antagonist, TLR-4 blocking antibodies, or overexpression of a dominant-negative form of the TLR-4 signaling adaptor TRIF-related adaptor molecule reduced nuclear factor-B activity but did not have a broad impact on the production of the mediators studied. In contrast, TLR-2 neutralizing antibodies inhibited nuclear factor-B activation (P<0.05) and significantly reduced monocyte chemotactic protein-1/CCL2 (P=0.000), IL-8/CXCL8 (P=0.009), IL-6 (P=0.000), and MMP-1 (P=0.000), MMP-2 (P=0.004), MMP-3 (P=0.000), and MMP-9 (P=0.006) production.
Conclusions— Our data indicate that TLR-2 signaling through MyD88 plays a predominant role in inflammation and matrix degradation in human atherosclerosis. TLR-2 blockade may represent a therapeutic strategy for atherosclerosis and its complications.
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Abstract 8 of 9 (Circulation. 2009;120:2470-2477.)
© 2009 American Heart Association, Inc.
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Vascular Medicine
Reduction of Circulating Soluble Fms-Like Tyrosine Kinase-1 Plays a Significant Role in Renal Dysfunction–Associated Aggravation of Atherosclerosis
Kenji Onoue, MD; Shiro Uemura, MD, PhD; Yukiji Takeda, MD, PhD; Satoshi Somekawa, MD, PhD; Hajime Iwama, MD, PhD; Keiichi Imagawa, PhD; Taku Nishida, MD; Yoshinobu Morikawa, MD; Yasuhiro Takemoto, MD; Osamu Asai, MD; Tsunenari Soeda, MD; Satoshi Okayama, MD; Kenichi Ishigami, MD; Kimihiko Nakatani, MD, PhD; Hiroyuki Kawata, MD, PhD; Manabu Horii, MD, PhD; Tamio Nakajima, MD, PhD; Yasuhiro Akai, MD, PhD; Masayuki Iwano, MD, PhD; Yoshihiko Saito, MD, PhD
From the First Department of Internal Medicine, Nara Medical University, Kashihara, Japan.
Correspondence to Shiro Uemura, First Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522 Japan. E-mail suemura@naramed-u.ac.jp
Received March 23, 2009; accepted October 9, 2009.
Background— Renal dysfunction is commonly accompanied by a worsening of atherosclerosis; however, the underlying molecular mechanism is not fully understood. We examined the role played by soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor (PlGF), in the worsening of atherosclerosis in patients with renal dysfunction and in an animal model of renal failure.
Methods and Results— In this study, 329 patients who received cardiac catheterization and 76 patients who underwent renal biopsy were enrolled. Both plasma sFlt-1 levels and renal sFlt-1 mRNA expression were positively correlated with estimated glomerular filtration rate (P<0.01). The PlGF/sFlt-1 ratio was negatively correlated with estimated glomerular filtration rate (P<0.01), whereas plasma PlGF levels were not affected by it. The PlGF/sFlt-1 ratio was significantly higher in patients with multivessel coronary artery disease than in patients with single-vessel or no coronary artery disease. The reduction of circulating sFlt-1 and renal sFlt-1 mRNA levels was confirmed in five-sixths (5/6)–nephrectomized apolipoprotein E–deficient mice that developed experimental renal dysfunction. Atherosclerotic plaque area and macrophage infiltration into the plaque were significantly higher in 5/6–nephrectomized apolipoprotein E–deficient mice than in control mice, but replacement therapy with recombinant sFlt-1 significantly reduced both plaque formation and macrophage infiltration.
Conclusions— The present study demonstrates that a reduction in the circulating levels of sFlt-1 is associated with the worsening of atherosclerosis that accompanies renal dysfunction.
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Abstract 9 of 9 (Circulation. 2009;120:2478-2487.)
© 2009 American Heart Association, Inc.
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Vascular Medicine
Impaired Fibrillin-1 Function Promotes Features of Plaque Instability in Apolipoprotein E–Deficient Mice
Jozef L. Van Herck, MD; Guido R.Y. De Meyer, PharmD, PhD; Wim Martinet, PhD; Cor E. Van Hove, Eng; Kenn Foubert, PharmD; Mart H. Theunis, PhD; Sandra Apers, PharmD, PhD; Hidde Bult, PhD; Christiaan J. Vrints, MD, PhD; Arnold G. Herman, MD, PhD
From the Division of Cardiology, Antwerp University Hospital, Edegem, Belgium (J.L.V.H., C.J.V.), and Division of Pharmacology (G.R.Y.D.M., W.M., C.E.V.H., H.B., A.G.H.) and Laboratory of Pharmacognosy and Pharmaceutical Analysis (K.F., M.H.T., S.A.), University of Antwerp, Wilrijk, Belgium.
Correspondence to Dr Jozef Van Herck, Antwerp University Hospital, Division of Cardiology, Wilrijkstraat 10, B-2650 Edegem, Belgium. E-mail jozef.vanherck@ua.ac.be
Received April 16, 2009; accepted October 2, 2009.
Background— Arterial stiffness has been associated with an increased cardiovascular risk. The aim of this study was to investigate the interaction between arterial stiffness and atherosclerosis.
Methods and Results— Mice with a mutation (C1039G+/–) in the fibrillin-1 gene leading to fragmentation of the elastic fibers were crossbred with apolipoprotein E–deficient (ApoE–/–) mice. Subsequently, ApoE–/– and ApoE–/–C1039G+/– mice were fed a Western-type diet for 10 or 20 weeks. Our results show that the interaction between arterial stiffness and atherosclerosis is bidirectional. On the one hand, arterial stiffness in ApoE–/–C1039G+/– mice increased more rapidly in the presence of atherosclerotic plaques. On the other hand, arterial stiffness promoted the development of larger and more unstable plaques in ApoE–/–C1039G+/– mice. The plaque area at the aortic root was increased 1.5- and 2.1-fold in ApoE–/–C1039G+/– mice after 10 and 20 weeks of Western-type diet, respectively. After 10 weeks of Western-type diet, plaques of ApoE–/–C1039G+/– mice showed increased apoptosis of smooth muscle cells, which was associated with a decrease in collagen content, an enlargement of the necrotic core, and an increase in macrophages. After 20 weeks of Western-type diet, the number of buried fibrous caps was increased in atherosclerotic lesions of ApoE–/–C1039G+/– mice, not only at the level of the aortic valves but also in the brachiocephalic artery and in the upper, middle, and lower thoracic aorta. Furthermore, acute plaque rupture was observed.
Conclusion— These results indicate that fragmentation of the elastic fibers leads to increased vascular stiffness, which promotes features of multifocal plaque instability.
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Abstract 1 of 9 (Circulation. 2009;120:2414-2420.)
© 2009 American Heart Association, Inc.
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Epidemiology and Prevention
Association of Circulating Cholesteryl Ester Transfer Protein Activity With Incidence of Cardiovascular Disease in the Community
Ramachandran S. Vasan, MD; Michael J. Pencina, PhD; Sander J. Robins, MD; Justin P. Zachariah, MD; Guneet Kaur, PhD; Ralph B. D'Agostino, PhD; Jose M. Ordovas, PhD
From the Framingham Heart Study, Framingham, Mass (R.S.V., M.J.P., S.J.R., R.B.D.); Department of Biostatistics, Boston University School of Public Health, Boston, Mass (M.J.P.); Department of Mathematics and Statistics, Boston University, Boston, Mass (M.J.P., G.K., R.B.D.); Preventive Medicine and Cardiology Sections, Department of Medicine, Boston University School of Medicine, Boston, Mass (R.S.V.); Department of Cardiology, Children’s Hospital Boston and Department of Pediatrics, Harvard Medical School, Boston, Mass (J.P.Z.); and Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Mass and Department of Cardiovascular Epidemiology and Population Genetics, National Center for Cardiovascular Investigation (CNIC), Madrid, Spain (J.M.O.).
Correspondence to Ramachandran S. Vasan, MD, Framingham Heart Study, 73 Mount Wayte Ave, Framingham, MA 01702-5803. E-mail vasan@bu.edu
Received April 11, 2009; accepted September 16, 2009.
Background— Plasma high-density lipoprotein cholesterol concentration is related inversely to the risk of cardiovascular disease (CVD). Inhibiting cholesteryl ester transfer protein (CETP) activity raises high-density lipoprotein cholesterol and may be cardioprotective, but an initial clinical trial with a CETP inhibitor was stopped prematurely because of increased CVD in treated patients, raising concerns about this approach. Data relating circulating CETP concentrations to CVD incidence in the community are conflicting.
Methods and Results— Plasma CETP activity was measured in 1978 Framingham Heart Study participants (mean age, 51 years; 54% women) who attended a routine examination in 1987–1990 and were free of CVD. On follow-up (mean, 15.1 years), 320 participants experienced a first CVD event (fatal or nonfatal coronary heart disease, cerebrovascular disease, peripheral vascular disease, or heart failure). In multivariable analyses adjusted for standard risk factors including high-density lipoprotein cholesterol, plasma CETP activity was related inversely to the incidence of CVD events (hazard ratio for activity, at or above the median of 0.72; 95% confidence interval, 0.57 to 0.90; P=0.004 [compared with below median]; hazard ratio per SD increment, 0.86; 95% confidence interval, 0.76 to 0.97; P=0.01). The inverse association of CETP activity with CVD incidence remained robust in time-dependent models updating standard risk factors every 4 years and was maintained in analyses of incident "hard" CVD events (myocardial infarction, stroke, or heart failure).
Conclusions— In our prospective investigation of a community-based sample, lower plasma CETP activity was associated with greater CVD risk. These observations, if confirmed, challenge the concept that CETP inhibition may lower CVD risk.
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Abstract 2 of 9 (Circulation. 2009;120:2421-2428.)
© 2009 American Heart Association, Inc.
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Epidemiology and Prevention
Glycemic Control and Cardiovascular Events in Diabetic Hemodialysis Patients
Christiane Drechsler, MD, MSc; Vera Krane, MD; Eberhard Ritz, MD; Winfried März, MD; Christoph Wanner, MD
From the University Hospital Würzburg, Department of Medicine 1, Division of Nephrology, Würzburg, Germany (C.D., V.K., C.W.); Leiden University Medical Center, Department of Clinical Epidemiology, Leiden, the Netherlands (C.D.); University Hospital Heidelberg, Department of Medicine, Division of Nephrology, Heidelberg, Germany (E.R.); Synlab Center of Laboratory Diagnostics, Heidelberg, Germany (W.M.); Medical University of Graz, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz, Austria (W.M.); and University of Heidelberg, Mannheim Institute of Public Health, Social and Preventive Medicine, Mannheim, Germany (W.M.).
Correspondence to Christiane Drechsler, MD, Department of Medicine, Division of Nephrology, University Hospital, Oberdürrbacherstrasse 6, D-97080 Würzburg, Germany. E-mail c.drechsler@gmx.net
Received February 11, 2009; accepted September 29, 2009.
Background— Patients on maintenance dialysis treatment experience an excess mortality, predominantly of sudden cardiac death. Poor glycemic control is associated with cardiovascular comorbidities in the general population. This study investigated the impact of glycemic control on cardiac and vascular outcomes in diabetic hemodialysis patients.
Methods and Results— Glycohemoglobin A1c (HbA1c) was measured in 1255 hemodialysis patients with type 2 diabetes mellitus who participated in the German Diabetes and Dialysis Study (4D Study) and were followed up for a median of 4 years. Using Cox regression analyses, we determined hazard ratios to reach prespecified, adjudicated end points according to HbA1c levels at baseline: sudden cardiac death (n=160), myocardial infarction (n=200), stroke (n=103), cardiovascular events (n=469), death caused by heart failure (n=41), and all-cause mortality (n=617). Patients had a mean age of 66±8 years (54% male) and mean HbA1c of 6.7±1.3%. Patients with an HbA1c >8% had a >2-fold higher risk of sudden death compared with those with an HbA1c 6% (hazard ratio, 2.14; 95% confidence interval, 1.33 to 3.44), persisting in multivariate models. With each 1% increase in HbA1c, the risk of sudden death rose significantly by 18%; similarly, cardiovascular events and mortality increased by 8%. There was a trend for higher risks of stroke and deaths resulting from heart failure, whereas myocardial infarction was not affected. The increased risks of both cardiovascular events and mortality were explained mainly by the impact of HbA1c on sudden death.
Conclusions— Poor glycemic control was strongly associated with sudden cardiac death in diabetic hemodialysis patients, which accounted for increased cardiovascular events and mortality. In contrast, myocardial infarction was not affected. Whether interventions achieving tight glycemic control decrease sudden death requires further evaluation.
Clinical Trial Registration— URL: http://www.clinicalstudyresults.org. Unique identifier: CT-981–423–239.
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Abstract 3 of 9 (Circulation. 2009;120:2429-2437.)
© 2009 American Heart Association, Inc.
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Epidemiology and Prevention
Differential Clinical Outcomes Associated With Hypoglycemia and Hyperglycemia in Acute Myocardial Infarction
Abhinav Goyal, MD, MHS; Shamir R. Mehta, MD, MSc; Rafael Díaz, MD; Hertzel C. Gerstein, MD, MSc; Rizwan Afzal, MSc; Denis Xavier, MD; Lisheng Liu, MD; Prem Pais, MD; Salim Yusuf, MBBS, DPhil
From the Population Health Research Institute (A.G., S.R.M., H.C.G., R.A., S.Y.), Hamilton Health Sciences, Hamilton, Ontario, Canada; Emory Schools of Public Health and Medicine (A.G.), Atlanta, Ga; Department of Medicine (S.R.M., H.C.G., S.Y.), McMaster University, Hamilton, Ontario, Canada; Estudios Cardiologicos Latinoamerica (R.D.), Rosario, Argentina; St John’s Medical College (D.X., P.P.), Bangalore, India; Cardiovascular Institute and Fu Wai Hospital (L.L.), Chinese Hypertension League Institute, Beijing, China.
Reprint requests to Abhinav Goyal, MD, MHS, 1518 Clifton Rd NE, Room 456, Atlanta, GA 30322. E-mail agoyal4@emory.edu
Received November 21, 2008; accepted October 2, 2009.
Background— In patients with acute myocardial infarction (AMI), hyperglycemia predicts death, but the prognostic significance of hypoglycemia is controversial.
Methods and Results— We evaluated the prognostic significance of hypoglycemia and hyperglycemia in 30 536 AMI patients in a post hoc analysis of 2 large trials of glucose-insulin-potassium therapy in AMI. Glucose levels on admission and at 6 and 24 hours after admission, as well as 30-day mortality, were documented. In separate multivariable Cox models for admission and postadmission glucose, we compared the prognostic value of hypoglycemia (70 mg/dL) and hyperglycemia (140 mg/dL) with normoglycemia (>70 and <140 mg/dL). Analyses were repeated with hypoglycemia defined as glucose 60 mg/dL and in key subgroups based on diabetes or insulin (glucose-insulin-potassium) allocation status. Both high and low percentiles of admission glucose predicted increased 30-day mortality. However, for postadmission glucose, this U-shaped relationship was attenuated so that only high and not low glucose levels remained prognostic. Hyperglycemia (140 mg/dL), both on admission (adjusted hazard ratio 1.43, 95% confidence interval 1.32 to 1.56, P<0.0001) and after admission (adjusted hazard ratio 1.47, 95% confidence interval 1.31 to 1.66, P<0.0001), predicted death compared with normoglycemia. In contrast, hypoglycemia (glucose 70 mg/dL) on admission was not prognostic (adjusted hazard ratio 1.16, 95% confidence interval 0.84 to 1.62, P=0.37), nor was postadmission hypoglycemia (adjusted hazard ratio 0.96, 95% confidence interval 0.72 to 1.26, P=0.75). Exploratory analyses that redefined hypoglycemia as glucose 60 mg/dL showed consistent results, as did analyses restricted to diabetic patients (18% of the study population). Postadmission hypoglycemia was more common in insulin (glucose-insulin-potassium)–treated patients (6.9%) than in untreated patients (3.4%) but did not predict mortality in either subgroup.
Conclusions— Both admission and postadmission hyperglycemia predict 30-day death in AMI patients. In contrast, only hypoglycemia on admission predicted death, and this relationship dissipated after admission. These data suggest hypoglycemia may not be a direct mediator of adverse outcomes in AMI patients.
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Abstract 4 of 9 (Circulation. 2009;120:2438-2447.)
© 2009 American Heart Association, Inc.
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Exercise Physiology
Physical Exercise Prevents Cellular Senescence in Circulating Leukocytes and in the Vessel Wall
Christian Werner, MD; Tobias Fürster, MD; Thomas Widmann, MD; Janine Pöss, MD; Cristiana Roggia, MD; Milad Hanhoun, MD; Jürgen Scharhag, MD; Nicole Büchner, DBBSc; Tim Meyer, MD; Wilfried Kindermann, MD; Judith Haendeler, PhD; Michael Böhm, MD; Ulrich Laufs, MD
From the Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin (C.W., T.F., J.P., M.H., M.B., U.L.), Klinik für Innere Medizin I, Onkologie, Hämatologie, Klinische Immunologie und Rheumatologie (T.W.), and Institut für Pathologie (C.R.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Institut für Sport und Präventivmedizin, Universität des Saarlandes, Saarbrücken (J.S., T.M., W.K.); and Institut für Umweltmedizinische Forschung at the Universität Düsseldorf gGmbH, Düsseldorf (N.B., J.H.), Germany.
Correspondence to Ulrich Laufs, MD, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66421 Homburg/Saar, Germany. E-mail ulrich@laufs.com
Received March 1, 2009; accepted October 9, 2009.
Background— The underlying molecular mechanisms of the vasculoprotective effects of physical exercise are incompletely understood. Telomere erosion is a central component of aging, and telomere-associated proteins regulate cellular senescence and survival. This study examines the effects of exercising on vascular telomere biology and endothelial apoptosis in mice and the effects of long-term endurance training on telomere biology in humans.
Methods and Results— C57/Bl6 mice were randomized to voluntary running or no running wheel conditions for 3 weeks. Exercise upregulated telomerase activity in the thoracic aorta and in circulating mononuclear cells compared with sedentary controls, increased vascular expression of telomere repeat-binding factor 2 and Ku70, and reduced the expression of vascular apoptosis regulators such as cell-cycle–checkpoint kinase 2, p16, and p53. Mice preconditioned by voluntary running exhibited a marked reduction in lipopolysaccharide-induced aortic endothelial apoptosis. Transgenic mouse studies showed that endothelial nitric oxide synthase and telomerase reverse transcriptase synergize to confer endothelial stress resistance after physical activity. To test the significance of these data in humans, telomere biology in circulating leukocytes of young and middle-aged track and field athletes was analyzed. Peripheral blood leukocytes isolated from endurance athletes showed increased telomerase activity, expression of telomere-stabilizing proteins, and downregulation of cell-cycle inhibitors compared with untrained individuals. Long-term endurance training was associated with reduced leukocyte telomere erosion compared with untrained controls.
Conclusions— Physical activity regulates telomere-stabilizing proteins in mice and in humans and thereby protects from stress-induced vascular apoptosis.
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Abstract 5 of 9 (Circulation. 2009;120:2448-2454.)
© 2009 American Heart Association, Inc.
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Genetics
Integrative Predictive Model of Coronary Artery Calcification in Atherosclerosis
Michael McGeachie, PhD; Rachel L. Badovinac Ramoni, DMD, ScD; Josyf C. Mychaleckyj, MA, DPhil; Karen L. Furie, MD, MPH; Jonathan M. Dreyfuss, MS; Yongmei Liu, PhD; David Herrington, MD, MHS; Xiuqing Guo, PhD; João A. Lima, MD; Wendy Post, MD, MS; Jerome I. Rotter, MD; Stephen Rich, PhD; Michèle Sale, PhD; Marco F. Ramoni, PhD
From the Children’s Hospital Informatics Program (M.M., J.M.D., M.F.R.), Harvard-MIT Division of Health Sciences and Technology, Boston, Mass; Harvard Partners Center for Genetics and Genomics (M.M., M.F.R.), Harvard Medical School, Boston, Mass; Department of Developmental Biology (R.L.B.R.), Harvard School of Dental Medicine, Boston, Mass; Center for Public Health Genomics (J.C.M., S.R., M.S.) and Department of Public Health Sciences (J.C.M., S.R.), University of Virginia, Charlottesville, Va; Department of Neurology (K.L.F.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass; Department of Epidemiology and Prevention (Y.L.) and Department of Internal Medicine (D.H.), Wake Forest University School of Medicine, Winston-Salem, NC; Medical Genetics Institute (X.G., J.I.R.), Cedars Sinai, Los Angeles, Calif; Donald W. Reynolds Cardiovascular Clinical Research Center (J.A.L., W.P.), Division of Cardiology, Johns Hopkins University, Baltimore, Md; and Department of Medicine (S.R., M.S.) and Department of Biochemistry and Molecular Genetics (M.S.), University of Virginia, Charlottesville, Va.
Correspondence to Marco F. Ramoni, PhD, Harvard Partners Center for Genetics and Genomics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, e-mail marco_ramoni@harvard.edu, or Michèle Sale, PhD, Center for Public Health Genomics, PO Box 800717, West Complex Room 6111, Charlottesville, VA 22908, e-mail ms5fe@virginia.edu
Received March 19, 2009; accepted September 28, 2009.
Background— Many different genetic and clinical factors have been identified as causes or contributors to atherosclerosis. We present a model of preclinical atherosclerosis based on genetic and clinical data that predicts the presence of coronary artery calcification in healthy Americans of European descent 45 to 84 years of age in the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods and Results— We assessed 712 individuals for the presence or absence of coronary artery calcification and assessed their genotypes for 2882 single-nucleotide polymorphisms. With the use of these single-nucleotide polymorphisms and relevant clinical data, a Bayesian network that predicts the presence of coronary calcification was constructed. The model contained 13 single-nucleotide polymorphisms (from genes AGTR1, ALOX15, INSR, PRKAB1, IL1R2, ESR2, KCNK1, FBLN5, PPARA, VEGFA, PON1, TDRD6, PLA2G7, and 1 ancestry informative marker) and 5 clinical variables (sex, age, weight, smoking, and diabetes mellitus) and achieved 85% predictive accuracy, as measured by area under the receiver operating characteristic curve. This is a significant (P<0.001) improvement on models that use just the single-nucleotide polymorphism data or just the clinical variables.
Conclusions— We present an investigation of joint genetic and clinical factors associated with atherosclerosis that shows predictive results for both cases, as well as enhanced performance for their combination.
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Abstract 6 of 9 (Circulation. 2009;120:2455-2461.)
© 2009 American Heart Association, Inc.
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Interventional Cardiology
Choice of Reperfusion Strategy at Hospitals With Primary Percutaneous Coronary Intervention
A National Registry of Myocardial Infarction Analysis
Reza Fazel, MD, MSc; Harlan M. Krumholz, MD, SM; Eric R. Bates, MD; William J. French, MD; Paul D. Frederick, MPH, MBA; Brahmajee K. Nallamothu, MD, MPH, for the National Registry of Myocardial Infarction (NRMI) Investigators
From the Department of Medicine, Division of Cardiology (R.F.), Emory University School of Medicine, Atlanta, Ga; Department of Medicine, Section of Cardiovascular Medicine and the Robert Wood Johnson Clinical Scholars Program, Department of Medicine, and the Section of Health Policy and Administration, School of Public Health, Yale University School of Medicine, and the Center for Outcomes Research and Evaluation, Yale–New Haven Hospital, all in New Haven, Conn (H.M.K); the Department of Internal Medicine, Division of Cardiovascular Medicine (E.R.B., B.K.N.), University of Michigan Medical School, Ann Arbor, Mich; Harbor-UCLA Medical Center (W.J.F.), Los Angeles, Calif; ICON Lifecycle Sciences Group (P.D.F.), San Francisco, Calif; and the Veterans Affairs Ann Arbor Health Services Research and Development Center of Excellence (B.K.N.), Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Mich.
Correspondence to Reza Fazel, MD, MSc, Emory University, Division of Cardiology, Bldg A, Suite 1-North, 1256 Briarcliff Rd NE, Atlanta, GA 30306. E-mail rfazel@emory.edu
Received February 25, 2009; accepted September 17, 2009.
Background— Many hospitals with percutaneous coronary intervention (PCI) capability also use fibrinolytic therapy in patients with ST-segment elevation myocardial infarction, but factors influencing the choice of reperfusion strategy at these hospitals are poorly understood. We examined clinical and system-related factors associated with choice of reperfusion strategy in patients with ST-segment elevation myocardial infarction at PCI-capable hospitals.
Methods and Results— We analyzed patients with ST-segment elevation myocardial infarction who presented to PCI-capable hospitals between July 1, 2000, and December 31, 2006, in the National Registry of Myocardial Infarction. Hierarchical multivariable logistic regression was used to examine the association between choice of reperfusion strategy and patient-, hospital-, and system-related factors. We identified 25 579 patients who received primary PCI and 14 332 patients who received fibrinolytic therapy at 444 PCI-capable hospitals. Use of reperfusion strategies varied widely across hospitals, although primary PCI use increased over the study period. Among the key clinical factors that favored primary PCI, cardiogenic shock and delayed presentation were associated with greater use of primary PCI (adjusted odds ratios 2.14 [95% confidence interval 1.72 to 2.66] and 1.18 [95% confidence interval 1.09 to 1.27], respectively), whereas a Thrombolysis in Myocardial Infarction risk score 5 was not. In contrast, female gender, advanced age, and nonwhite race, all risk factors for intracranial hemorrhage after fibrinolytic therapy, were not associated with increased use of primary PCI. Off-hours presentation had the strongest association overall, with an 70% lower likelihood of patients undergoing primary PCI (adjusted odds ratio 0.27, 95% confidence interval 0.25 to 0.29).
Conclusions— Use of primary PCI, although increasing over recent years, is not universal at PCI-capable hospitals, and optimization of its use at such hospitals represents a potential opportunity to improve outcomes in patients with ST-segment elevation myocardial infarction.
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Abstract 7 of 9 (Circulation. 2009;120:2462-2469.)
© 2009 American Heart Association, Inc.
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Vascular Medicine
Toll-Like Receptor-2 Mediates Inflammation and Matrix Degradation in Human Atherosclerosis
Claudia Monaco, MD, PhD, FESC; Scott M. Gregan, BSc; Tina J. Navin, BSc; Brian M.J. Foxwell, PhD, DSc, FRCPath; Alun H. Davies, MA, BM, BCh, DM, FRCS, FHEA; Marc Feldmann, MB, BS, BSc, PhD, FRCPath, FRCP, F***, FAA, FRS
From the Kennedy Institute of Rheumatology (C.M., S.M.G., T.J.N., B.M.J.F., M.F.) and Surgery, Oncology, Reproductive Biology, and Anesthetic Divisions (C.M., T.J.N., A.H.D.), Faculty of Medicine, Imperial College, London, United Kingdom.
Correspondence to Dr Marc Feldmann or Dr Claudia Monaco, Kennedy Institute of Rheumatology Division, Imperial College, 65 Aspenlea Rd, London W6 8LH, UK. E-mail m.feldmann@imperial.ac.uk or c.monaco@imperial.ac.uk
Received January 22, 2009; accepted October 5, 2009.
Background— Inflammation and matrix degradation are the hallmarks of high-risk atherosclerosis that leads to myocardial infarction and stroke. Toll-like receptors (TLRs), key players in innate immunity, are upregulated in atherosclerotic lesions, but their functional role in human atherosclerosis is unknown. We explored the effects of blocking TLR-2, TLR-4, and myeloid differentiation primary response gene 88 (MyD88), a signaling adaptor shared by most TLRs and interleukin-1 receptor (IL-1R), in an in vitro model of human atherosclerosis.
Methods and Results— Carotid endarterectomies were obtained from patients with symptomatic carotid disease. Cells were isolated via enzymatic tissue dissociation and cultured in the presence or absence of TLR signaling blockers. A dominant-negative form of MyD88 (MyD88DN) decreased the production of monocyte chemotactic protein-1/CCL2 (P=0.000), IL-8/CXCL8 (P=0.006), IL-6 (P=0.002), matrix metalloproteinase-1 (MMP-1; P=0.002), and MMP-3 (P=0.000), as well as nuclear factor-B activation (P<0.05) in atheroma cell cultures. IL-1R antagonist, TLR-4 blocking antibodies, or overexpression of a dominant-negative form of the TLR-4 signaling adaptor TRIF-related adaptor molecule reduced nuclear factor-B activity but did not have a broad impact on the production of the mediators studied. In contrast, TLR-2 neutralizing antibodies inhibited nuclear factor-B activation (P<0.05) and significantly reduced monocyte chemotactic protein-1/CCL2 (P=0.000), IL-8/CXCL8 (P=0.009), IL-6 (P=0.000), and MMP-1 (P=0.000), MMP-2 (P=0.004), MMP-3 (P=0.000), and MMP-9 (P=0.006) production.
Conclusions— Our data indicate that TLR-2 signaling through MyD88 plays a predominant role in inflammation and matrix degradation in human atherosclerosis. TLR-2 blockade may represent a therapeutic strategy for atherosclerosis and its complications.
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Abstract 8 of 9 (Circulation. 2009;120:2470-2477.)
© 2009 American Heart Association, Inc.
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Vascular Medicine
Reduction of Circulating Soluble Fms-Like Tyrosine Kinase-1 Plays a Significant Role in Renal Dysfunction–Associated Aggravation of Atherosclerosis
Kenji Onoue, MD; Shiro Uemura, MD, PhD; Yukiji Takeda, MD, PhD; Satoshi Somekawa, MD, PhD; Hajime Iwama, MD, PhD; Keiichi Imagawa, PhD; Taku Nishida, MD; Yoshinobu Morikawa, MD; Yasuhiro Takemoto, MD; Osamu Asai, MD; Tsunenari Soeda, MD; Satoshi Okayama, MD; Kenichi Ishigami, MD; Kimihiko Nakatani, MD, PhD; Hiroyuki Kawata, MD, PhD; Manabu Horii, MD, PhD; Tamio Nakajima, MD, PhD; Yasuhiro Akai, MD, PhD; Masayuki Iwano, MD, PhD; Yoshihiko Saito, MD, PhD
From the First Department of Internal Medicine, Nara Medical University, Kashihara, Japan.
Correspondence to Shiro Uemura, First Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522 Japan. E-mail suemura@naramed-u.ac.jp
Received March 23, 2009; accepted October 9, 2009.
Background— Renal dysfunction is commonly accompanied by a worsening of atherosclerosis; however, the underlying molecular mechanism is not fully understood. We examined the role played by soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor (PlGF), in the worsening of atherosclerosis in patients with renal dysfunction and in an animal model of renal failure.
Methods and Results— In this study, 329 patients who received cardiac catheterization and 76 patients who underwent renal biopsy were enrolled. Both plasma sFlt-1 levels and renal sFlt-1 mRNA expression were positively correlated with estimated glomerular filtration rate (P<0.01). The PlGF/sFlt-1 ratio was negatively correlated with estimated glomerular filtration rate (P<0.01), whereas plasma PlGF levels were not affected by it. The PlGF/sFlt-1 ratio was significantly higher in patients with multivessel coronary artery disease than in patients with single-vessel or no coronary artery disease. The reduction of circulating sFlt-1 and renal sFlt-1 mRNA levels was confirmed in five-sixths (5/6)–nephrectomized apolipoprotein E–deficient mice that developed experimental renal dysfunction. Atherosclerotic plaque area and macrophage infiltration into the plaque were significantly higher in 5/6–nephrectomized apolipoprotein E–deficient mice than in control mice, but replacement therapy with recombinant sFlt-1 significantly reduced both plaque formation and macrophage infiltration.
Conclusions— The present study demonstrates that a reduction in the circulating levels of sFlt-1 is associated with the worsening of atherosclerosis that accompanies renal dysfunction.
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Abstract 9 of 9 (Circulation. 2009;120:2478-2487.)
© 2009 American Heart Association, Inc.
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Vascular Medicine
Impaired Fibrillin-1 Function Promotes Features of Plaque Instability in Apolipoprotein E–Deficient Mice
Jozef L. Van Herck, MD; Guido R.Y. De Meyer, PharmD, PhD; Wim Martinet, PhD; Cor E. Van Hove, Eng; Kenn Foubert, PharmD; Mart H. Theunis, PhD; Sandra Apers, PharmD, PhD; Hidde Bult, PhD; Christiaan J. Vrints, MD, PhD; Arnold G. Herman, MD, PhD
From the Division of Cardiology, Antwerp University Hospital, Edegem, Belgium (J.L.V.H., C.J.V.), and Division of Pharmacology (G.R.Y.D.M., W.M., C.E.V.H., H.B., A.G.H.) and Laboratory of Pharmacognosy and Pharmaceutical Analysis (K.F., M.H.T., S.A.), University of Antwerp, Wilrijk, Belgium.
Correspondence to Dr Jozef Van Herck, Antwerp University Hospital, Division of Cardiology, Wilrijkstraat 10, B-2650 Edegem, Belgium. E-mail jozef.vanherck@ua.ac.be
Received April 16, 2009; accepted October 2, 2009.
Background— Arterial stiffness has been associated with an increased cardiovascular risk. The aim of this study was to investigate the interaction between arterial stiffness and atherosclerosis.
Methods and Results— Mice with a mutation (C1039G+/–) in the fibrillin-1 gene leading to fragmentation of the elastic fibers were crossbred with apolipoprotein E–deficient (ApoE–/–) mice. Subsequently, ApoE–/– and ApoE–/–C1039G+/– mice were fed a Western-type diet for 10 or 20 weeks. Our results show that the interaction between arterial stiffness and atherosclerosis is bidirectional. On the one hand, arterial stiffness in ApoE–/–C1039G+/– mice increased more rapidly in the presence of atherosclerotic plaques. On the other hand, arterial stiffness promoted the development of larger and more unstable plaques in ApoE–/–C1039G+/– mice. The plaque area at the aortic root was increased 1.5- and 2.1-fold in ApoE–/–C1039G+/– mice after 10 and 20 weeks of Western-type diet, respectively. After 10 weeks of Western-type diet, plaques of ApoE–/–C1039G+/– mice showed increased apoptosis of smooth muscle cells, which was associated with a decrease in collagen content, an enlargement of the necrotic core, and an increase in macrophages. After 20 weeks of Western-type diet, the number of buried fibrous caps was increased in atherosclerotic lesions of ApoE–/–C1039G+/– mice, not only at the level of the aortic valves but also in the brachiocephalic artery and in the upper, middle, and lower thoracic aorta. Furthermore, acute plaque rupture was observed.
Conclusion— These results indicate that fragmentation of the elastic fibers leads to increased vascular stiffness, which promotes features of multifocal plaque instability.
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