Inflammation and Insulin Resistance in PAD

Summary

Principal Investigator: Mark Creager
Abstract: Patients with peripheral arterial disease (PAD) frequently have functional limitations and symptoms of claudication that impact adversely on their quality of life. Many progress to critical limb ischemia requiring revascularization. Vascular inflammation and insulin resistance are two important and interdependent conditions that are associated with atherosclerosis. Moreover, both inflammation and insulin resistance cause abnormalities in vascular function and insulin resistance interferes with skeletal muscle metabolism. As such, inflammation and insulin resistance provide attractive targets for therapy that could potentially ameliorate the development of symptomatic PAD or improve the function and clinical outcomes of patients with PAD. Accordingly, the applicants propose three specific aims to determine whether inflammation and insulin resistance contribute to the functional and clinical consequences of PAD. First, a prospective, nested, case-control evaluation will be performed to test the hypothesis that baseline plasma levels of inflammatory cytokines (e.g. interleukin (IL)-4, IL-6, IL-18, macrophage inhibiting cytokine-1, CD 40 ligand) among healthy men are associated with the development of future symptomatic PAD. Second, to test the hypothesis that inflammation and insulin resistance contribute to reduced walking distance in patients with intermittent claudication by impairing vascular reactivity and skeletal muscle metabolic function, plasma markers of inflammation and insulin resistance, endothelium-dependent and independent vasodilation (by vascular ultrasonography) and skeletal muscle glucose utilization (by [18F] FDG positron emission tomography) will be measured before and after 12 weeks of treatment with rosiglitazone, atorvastatin or placebo in a 2x2 factorial design protocol. Third, to test the hypothesis that inflammation and insulin resistance are associated with the incidence and progression of vein graft disease in patients undergoing lower extremity vein bypass, functional and morphologic changes in vein grafts (measured by ultrasound and magnetic resonance imaging) will be assessed and related to inflammation and insulin resistance and to a composite clinical outcome of graft occlusion, re-intervention or major amputation. It is anticipated that the findings from this investigation will uncover novel pathophysiologic mechanisms and foster a new paradigm for the treatment of PAD.
Funding Period: 2003-09-22 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. pmc A single nucleotide polymorphism in the p27(Kip1) gene is associated with primary patency of lower extremity vein bypass grafts
    Michael S Conte
    Division of Vascular and Endovascular Surgery, University of California, San Francisco, San Francisco, Calif 94143, USA
    J Vasc Surg 57:1179-85.e1-2. 2013
  2. pmc Thirty-day vein remodeling is predictive of midterm graft patency after lower extremity bypass
    Warren J Gasper
    Division of Vascular and Endovascular Surgery, Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94143 0222, USA
    J Vasc Surg 57:9-18. 2013
  3. pmc Sex-based differences in the inflammatory profile of peripheral artery disease and the association with primary patency of lower extremity vein bypass grafts
    Jade S Hiramoto
    Division of Vascular and Endovascular Surgery, University of California San Francisco, San Francisco, CA 94143 0222, USA
    J Vasc Surg 56:387-95; discussion 395. 2012
  4. pmc An integrated biochemical prediction model of all-cause mortality in patients undergoing lower extremity bypass surgery for advanced peripheral artery disease
    Christopher D Owens
    Division of Vascular and Endovascular Surgery, University of California, San Francisco, San Francisco, Calif 94148, USA
    J Vasc Surg 56:686-95. 2012
  5. pmc Aspirin-triggered lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis
    Karen J Ho
    Division of Vascular and Endovascular Surgery, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, USA
    Am J Pathol 177:2116-23. 2010
  6. ncbi Impaired skeletal muscle glucose uptake by [18F]fluorodeoxyglucose-positron emission tomography in patients with peripheral artery disease and intermittent claudication
    Reena L Pande
    Brigham and Women s Hospital, Boston, MA 02115, USA
    Arterioscler Thromb Vasc Biol 31:190-6. 2011
  7. pmc Chemical mediators of inflammation and resolution in post-operative abdominal aortic aneurysm patients
    Padmini S Pillai
    Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Inflammation 35:98-113. 2012
  8. ncbi The PPAR-RXR transcriptional complex in the vasculature: energy in the balance
    Jorge Plutzky
    Cardiovascular Medicine, Brigham and Women s Hospital, Boston, MA, USA
    Circ Res 108:1002-16. 2011
  9. pmc Smoking, smoking cessation, [corrected] and risk for symptomatic peripheral artery disease in women: a cohort study
    David Conen
    University Hospital, Basel, Switzerland
    Ann Intern Med 154:719-26. 2011
  10. pmc Secondary prevention and mortality in peripheral artery disease: National Health and Nutrition Examination Study, 1999 to 2004
    Reena L Pande
    Cardiovascular Division, Brigham and Women s Hospital, 75 Francis St, Boston, MA 02115, USA
    Circulation 124:17-23. 2011

Scientific Experts

  • Dimitris Mitsouras
  • Reena L Pande
  • J Plutzky
  • Frank John Rybicki
  • Christopher D Owens
  • Todd Perlstein
  • MICHAEL SALVATORE CONTE
  • Mark A Creager
  • Paul M Ridker
  • Aruna D Pradhan
  • David Conen
  • Ji Min Kim
  • Warren J Gasper
  • Michael Belkin
  • Jade S Hiramoto
  • Padmini S Pillai
  • Deborah Y Ho
  • Tiffany M Powell
  • Julie E Buring
  • Charles N Serhan
  • Akm Khyrul Wara
  • Karen J Ho
  • W Ahmed
  • Nancy Hills
  • John Boscardin
  • Stanley Leeson
  • Timothy F Porter
  • Simon Gelman
  • Basak Icli
  • Brendan M Everett
  • Thomas C Spelsberg
  • Fehim Esen
  • ShiYin Foo
  • Eunjung Kim
  • Kevin Croce
  • Yevgenia Tesmenitsky
  • Jung Soo Lee
  • Dorit Leshem-Lev
  • Anthony Rosenzweig
  • Xinghui Sun
  • Malayannan Subramaniam
  • Robert J Glynn
  • Mark W Feinberg
  • Nancy R Cook
  • Tobias Kurth
  • Eli I Lev
  • Kathryn A Britton
  • Alex H K Kroemer
  • Hope Lancero
  • Matthew Spite
  • Kathryn M Rexrode
  • T Kanda
  • J Brown
  • M Kadakia
  • M Sharlach
  • P Devchand
  • F Zandbergen
  • O Ziouzenkova
  • S Francis
  • G Orasanu

Detail Information

Publications29

  1. pmc A single nucleotide polymorphism in the p27(Kip1) gene is associated with primary patency of lower extremity vein bypass grafts
    Michael S Conte
    Division of Vascular and Endovascular Surgery, University of California, San Francisco, San Francisco, Calif 94143, USA
    J Vasc Surg 57:1179-85.e1-2. 2013
    ..We hypothesized an association with vein graft patency...
  2. pmc Thirty-day vein remodeling is predictive of midterm graft patency after lower extremity bypass
    Warren J Gasper
    Division of Vascular and Endovascular Surgery, Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94143 0222, USA
    J Vasc Surg 57:9-18. 2013
    ..Successful adaptation of a vein graft to an arterial environment is incompletely understood. We sought to investigate whether early vein graft remodeling is predictive of subsequent patency...
  3. pmc Sex-based differences in the inflammatory profile of peripheral artery disease and the association with primary patency of lower extremity vein bypass grafts
    Jade S Hiramoto
    Division of Vascular and Endovascular Surgery, University of California San Francisco, San Francisco, CA 94143 0222, USA
    J Vasc Surg 56:387-95; discussion 395. 2012
    ..This study was conducted to determine if there are sex-based differences in the inflammatory phenotype of patients undergoing lower extremity bypass (LEB) and if they correlate with clinical outcomes...
  4. pmc An integrated biochemical prediction model of all-cause mortality in patients undergoing lower extremity bypass surgery for advanced peripheral artery disease
    Christopher D Owens
    Division of Vascular and Endovascular Surgery, University of California, San Francisco, San Francisco, Calif 94148, USA
    J Vasc Surg 56:686-95. 2012
    ..This study tested the hypothesis that baseline biochemical parameters would add clinically meaningful predictive information in patients undergoing lower extremity bypass operations...
  5. pmc Aspirin-triggered lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis
    Karen J Ho
    Division of Vascular and Endovascular Surgery, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, USA
    Am J Pathol 177:2116-23. 2010
    ..These results also suggest that peripheral artery disease is associated with an inflammation-resolution deficit and highlight a potential therapeutic opportunity for the regulation of vascular injury responses...
  6. ncbi Impaired skeletal muscle glucose uptake by [18F]fluorodeoxyglucose-positron emission tomography in patients with peripheral artery disease and intermittent claudication
    Reena L Pande
    Brigham and Women s Hospital, Boston, MA 02115, USA
    Arterioscler Thromb Vasc Biol 31:190-6. 2011
    ..We aimed to determine whether skeletal muscle glucose uptake, assessed by [(18)F]fluorodeoxyglucose positron emission tomography, is reduced in patients with claudication...
  7. pmc Chemical mediators of inflammation and resolution in post-operative abdominal aortic aneurysm patients
    Padmini S Pillai
    Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Inflammation 35:98-113. 2012
    ..Together, these translational metabolomic profiles demonstrate for the first time the temporal relationships between local mediators in humans relevant in inflammation resolution...
  8. ncbi The PPAR-RXR transcriptional complex in the vasculature: energy in the balance
    Jorge Plutzky
    Cardiovascular Medicine, Brigham and Women s Hospital, Boston, MA, USA
    Circ Res 108:1002-16. 2011
    ..Both the basic science data and the clinical experience with PPAR agonists identify the need to better understand these important transcriptional regulators...
  9. pmc Smoking, smoking cessation, [corrected] and risk for symptomatic peripheral artery disease in women: a cohort study
    David Conen
    University Hospital, Basel, Switzerland
    Ann Intern Med 154:719-26. 2011
    ..Smoking has a well-documented detrimental effect on risk for myocardial infarction and stroke, but less information is available regarding peripheral artery disease (PAD), particularly among women...
  10. pmc Secondary prevention and mortality in peripheral artery disease: National Health and Nutrition Examination Study, 1999 to 2004
    Reena L Pande
    Cardiovascular Division, Brigham and Women s Hospital, 75 Francis St, Boston, MA 02115, USA
    Circulation 124:17-23. 2011
    ..We aimed to determine the number of US adults with PAD who are not receiving preventive therapies and whether treatment is associated with reduced mortality in PAD subjects without known cardiovascular disease...
  11. pmc The relative importance of systolic versus diastolic blood pressure control and incident symptomatic peripheral artery disease in women
    Tiffany M Powell
    Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390 9047, USA
    Vasc Med 16:239-46. 2011
    ..In conclusion, these prospective data suggest a strong prognostic role for uncontrolled blood pressure and, particularly, uncontrolled systolic blood pressure in the development of peripheral atherosclerosis in women...
  12. pmc TGF-β1 signaling and Krüppel-like factor 10 regulate bone marrow-derived proangiogenic cell differentiation, function, and neovascularization
    Akm Khyrul Wara
    Department of Medicine, Cardiovascular Division, Brigham and Women s Hospital, Harvard Medical School, Boston, MA, USA
    Blood 118:6450-60. 2011
    ..Collectively, these observations identify TGF-β1 signaling and KLF10 as key regulators of functional PACs derived from CMPs and GMPs and may provide a therapeutic target during cardiovascular ischemic states...
  13. pmc High-molecular-weight and total adiponectin levels and incident symptomatic peripheral artery disease in women: a prospective investigation
    Deborah Y Ho
    Division of Preventive Medicine, Brigham and Women s Hospital, 900 Commonwealth Ave E, Boston, MA 02215, USA
    Circulation 124:2303-11. 2011
    ..To our knowledge, no prior prospective studies have evaluated adiponectin, including high-molecular-weight (HMW) adiponectin, and incident peripheral artery disease (PAD)...
  14. ncbi Multi-contrast high spatial resolution black blood inner volume three-dimensional fast spin echo MR imaging in peripheral vein bypass grafts
    Frank J Rybicki
    Applied Imaging Science Laboratory, Department of Radiology, Brigham and Women s Hospital, Boston, MA, USA
    Int J Cardiovasc Imaging 26:683-91. 2010
    ..Vessel wall area differences suggest that LE-PVBG vessel wall tissues produce distinct signal characteristics under T1 and T2 MR contrast weightings...
  15. pmc Novel adipokines, high molecular weight adiponectin and resistin, are associated with outcomes following lower extremity revascularization with autogenous vein
    Christopher D Owens
    Division of Vascular and Endovascular Surgery, University of California, San Francisco, Calif, USA
    J Vasc Surg 51:1152-9. 2010
    ..We hypothesized that serum biomarkers of insulin resistance and inflammation would identify a subgroup at elevated risk for graft failure, limb loss, and mortality...
  16. pmc Adaptive changes in autogenous vein grafts for arterial reconstruction: clinical implications
    Christopher D Owens
    Division of Vascular and Endovascular Surgery, University of California San Francisco, San Francisco, CA 94143, USA
    J Vasc Surg 51:736-46. 2010
    ..This review summarizes recent translational efforts to understand the structural and functional properties of human vein grafts and places it within the context of the rich existing literature of vein graft failure...
  17. pmc In vivo differentiation of two vessel wall layers in lower extremity peripheral vein bypass grafts: application of high-resolution inner-volume black blood 3D FSE
    Dimitris Mitsouras
    Department of Radiology, Applied Imaging Science Laboratory, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Magn Reson Med 62:607-15. 2009
    ....
  18. pmc Elevated C-reactive protein levels are associated with postoperative events in patients undergoing lower extremity vein bypass surgery
    Christopher D Owens
    Division of Vascular Surgery, Brigham and Women s Hospital, Boston, MA 02115, USA
    J Vasc Surg 45:2-9; discussion 9. 2007
    ..We hypothesized that high levels of inflammatory markers would identify patients at increased risk for adverse events (graft failure, major cardiovascular events) after lower extremity bypass surgery...
  19. ncbi Molecular engineering of vein bypass grafts
    Michael S Conte
    Department of Vascular and Endovascular Surgery, Brigham and Women s Hospital, Boston, MA 02115, USA
    J Vasc Surg 45:A74-81. 2007
    ..A better understanding of the remodeling response of vein grafts in humans is required to design effective molecular therapies and to define the appropriate target populations and surrogate markers for future clinical trials...
  20. ncbi PPARs and their metabolic modulation: new mechanisms for transcriptional regulation?
    W Ahmed
    Cardiovascular Division, Harvard Medical School, Brigham and Women s Hospital, Boston, MA, USA
    J Intern Med 262:184-98. 2007
    ....
  21. ncbi Serum total bilirubin level and prevalent lower-extremity peripheral arterial disease: National Health and Nutrition Examination Survey (NHANES) 1999 to 2004
    Todd S Perlstein
    Brigham and Women s Hospital, Cardiovascular Division, Harvard Medical School, Boston, MA 02115, USA
    Arterioscler Thromb Vasc Biol 28:166-72. 2008
    ..We hypothesized that higher levels of bilirubin would reduce susceptibility to peripheral arterial disease (PAD)...
  22. ncbi High-resolution peripheral vein bypass graft wall studies using high sampling efficiency inner volume 3D FSE
    Dimitris Mitsouras
    Cardiovascular Imaging Section, Department of Radiology, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Magn Reson Med 59:650-4. 2008
    ....
  23. ncbi Lower extremity vein graft failure: a translational approach
    Christopher D Owens
    Division of Vascular and Endovascular Surgery, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Vasc Med 13:63-74. 2008
    ..This article reviews the definition and diagnosis of vein graft failure and summarizes our current efforts to understand the mechanisms of normal and abnormal vein graft adaptation to the arterial environment...
  24. pmc Early remodeling of lower extremity vein grafts: inflammation influences biomechanical adaptation
    Christopher D Owens
    Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02215, USA
    J Vasc Surg 47:1235-42. 2008
    ..We sought to examine the hypothesis that systemic inflammation influences this early remodeling response...
  25. pmc Association of insulin resistance and inflammation with peripheral arterial disease: the National Health and Nutrition Examination Survey, 1999 to 2004
    Reena L Pande
    Brigham and Women s Hospital, Cardiovascular Division, 75 Francis St, A Bldg, 3rd Floor, Boston, MA 02115, USA
    Circulation 118:33-41. 2008
    ..We hypothesized that IR is associated with PAD and that the presence of IR would influence the association between C-reactive protein (CRP) and PAD, an association established predominantly in healthy individuals...
  26. pmc Serum total bilirubin level, prevalent stroke, and stroke outcomes: NHANES 1999-2004
    Todd S Perlstein
    Department of Medicine, Cardiovascular Division, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Am J Med 121:781-788.e1. 2008
    ..Clinical data addressing the association of bilirubin with stroke are not available. We hypothesized that higher bilirubin levels would be associated with reduced stroke prevalence and improved stroke outcomes...
  27. pmc Metabolic syndrome, inflammation, and risk of symptomatic peripheral artery disease in women: a prospective study
    David Conen
    Center for Cardiovascular Disease Prevention, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02215, USA
    Circulation 120:1041-7. 2009
    ..We therefore evaluated the relationship between MetS, inflammation, and incident PAD...
  28. ncbi Early biomechanical changes in lower extremity vein grafts--distinct temporal phases of remodeling and wall stiffness
    Christopher D Owens
    Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    J Vasc Surg 44:740-6. 2006
    ..The geometric and biomechanical changes that contribute to vein graft remodeling are not well established. We sought to measure patterns of adaptation in lower extremity vein grafts and assess their correlation with clinical outcomes...