Skip to main content
  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

  • Home
  • About this Journal
    • Editorial Board
    • Meet the Editors
    • Editorial Manifesto
    • Impact Factor
    • Journal History
    • General Statistics
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • Circulation Research Profiles
    • Trainees & Young Investigators
    • Research Around the World
    • News & Views
    • The NHLBI Page
    • Viewpoints
    • Compendia
    • Reviews
    • Recent Review Series
    • Profiles in Cardiovascular Science
    • Leaders in Cardiovascular Science
    • Commentaries on Cutting Edge Science
    • AHA/BCVS Scientific Statements
    • Abstract Supplements
    • Circulation Research Classics
    • In This Issue Archive
    • Anthology of Images
  • Resources
    • Online Submission/Peer Review
    • Why Submit to Circulation Research
    • Instructions for Authors
    • → Article Types
    • → Manuscript Preparation
    • → Submission Tips
    • → Journal Policies
    • Circulation Research Awards
    • Image Gallery
    • Council on Basic Cardiovascular Sciences
    • Customer Service & Ordering Info
    • International Users
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
  • Impact Factor 13.965
  • Facebook
  • Twitter

  • My alerts
  • Sign In
  • Join

  • Advanced search

Header Publisher Menu

  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

Circulation Research

  • My alerts
  • Sign In
  • Join

  • Impact Factor 13.965
  • Facebook
  • Twitter
  • Home
  • About this Journal
    • Editorial Board
    • Meet the Editors
    • Editorial Manifesto
    • Impact Factor
    • Journal History
    • General Statistics
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • Circulation Research Profiles
    • Trainees & Young Investigators
    • Research Around the World
    • News & Views
    • The NHLBI Page
    • Viewpoints
    • Compendia
    • Reviews
    • Recent Review Series
    • Profiles in Cardiovascular Science
    • Leaders in Cardiovascular Science
    • Commentaries on Cutting Edge Science
    • AHA/BCVS Scientific Statements
    • Abstract Supplements
    • Circulation Research Classics
    • In This Issue Archive
    • Anthology of Images
  • Resources
    • Online Submission/Peer Review
    • Why Submit to Circulation Research
    • Instructions for Authors
    • → Article Types
    • → Manuscript Preparation
    • → Submission Tips
    • → Journal Policies
    • Circulation Research Awards
    • Image Gallery
    • Council on Basic Cardiovascular Sciences
    • Customer Service & Ordering Info
    • International Users
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
Editorial

Transforming Growth Factor-β

A Local or Systemic Mediator of Plaque Stability?

Esther Lutgens, Mat J.A.P. Daemen
Download PDF
Circulation Research. 2001;89:853-855
Originally published November 9, 2001
Esther Lutgens
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mat J.A.P. Daemen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics

Jump to

  • Article
    • Acknowledgments
    • Footnotes
    • References
  • Info & Metrics
  • eLetters
Loading
  • atherosclerosis
  • inflammation
  • fibrosis
  • transforming growth factor-β
  • unstable plaque

See related article, pages 930–934

Atherosclerosis is mainly considered to be a chronic inflammatory disease.1,2 The importance of inflammatory mediators in the initiation and progression of atherosclerosis is reflected by the composition of the atherosclerotic lesion and by many intervention studies in mouse models of atherosclerosis. Activated macrophages and T-lymphocytes are already observed in fatty streak lesions,3 and the contribution of inflammatory cells and mediators increases when the atherosclerotic lesion progresses.4 Furthermore, intervention studies in atherosclerotic mouse models that inhibit major (anti)inflammatory mediators such as CD40L,5–9 gm-CSF,10,11 MCP1,12 IFNγ,13 and IL-1014,15 have a profound effect on lesion initiation, progression, and plaque composition.

So far, IL-10 is the only antiinflammatory cytokine that has been reported to be protective in atherosclerosis.15,16 In the present issue of Circulation Research, the study by Mallat et al17 showed that inhibition of the antiinflammatory cytokine transforming growth factor (TGF)-β resulted in an acceleration of atherosclerosis. Moreover, atherosclerotic lesions exhibited an increased inflammatory cell content and a decrease in collagen content, which are features of plaque instability. The data of Mallat et al indicate that TGF-β plays a protective role in the initiation of atherosclerosis and may be an important factor for the maintenance of plaque stability.

The feature that inhibition of inflammatory mediators or stimulation of antiinflammatory mediators modulate atherosclerotic plaque stability has already been shown in several studies. For example, interventions in atherosclerotic mouse models with major inflammatory regulators such as CD40L,5,6,8,9 IFNγ,13 and IL1014 are able to modulate features of plaque stability, such as the amount of inflammation and fibrosis. IFNγ −/−/ApoE −/− mice show a decreased inflammatory cell content and an increased collagen-content,13 whereas inhibition of the antiinflammatory cytokine IL-10 showed the reverse.14

The inflammatory mediator with the most profound effect on plaque stability is CD40L. Besides a profound decrease in plaque area, deficiency of a functional CD40L gene resulted in a less lipid-containing, collagen- and smooth muscle cell–rich plaque phenotype, with a reduced macrophage and T-lymphocyte content in their advanced atherosclerotic plaques.5,7 In follow-up studies, pharmacological interruption of CD40L-CD40 signaling (anti-CD40L antibody) induced a quite similar phenotype.6,7,9 This phenotype could even be established when the antibody treatment was delayed until advanced plaques had developed.

Further dissection of the pathways involved in the development of the stable plaque phenotype revealed an increased immunoreactivity of TGF-β.6 These data suggest a key role for TGF-β in the development of a stable plaque phenotype during CD40L inhibition. Moreover, with the data of Mallat et al,17 a key role for TGF-β in the regulation of plaque stability in general can been proposed.

The first evidence for an important role for TGF-β in vascular biology has been shown in studies in the balloon-injured rat carotid artery, a model for neointima formation. TGF-β levels had increased during the first day after the procedure.18 Furthermore, overexpression or inhibition of TGF-β influenced the extent of neointima formation, extracellular matrix deposition, or smooth muscle cell proliferation.19,20

Although the effects of TGF-β on neointimal formation have been extensively investigated, data regarding the effects of TGF-β on primary atherosclerosis are still limited and, moreover, solely descriptive. The localization of the different isoforms of TGF-β and its receptors in the atherosclerotic plaque are well described. TGF-β1 and -β3 are present in all stages of atherosclerosis and are predominantly expressed by the macrophage and the smooth muscle cell.21,22 On the other hand, TGF-βRI and -βRII are abundantly present in fatty streaks, whereas only low, patchy expression is observed in advanced atherosclerotic lesions.23 Interestingly, mutations in the TGF-βRII that disable proper signaling in atherosclerotic lesions have also been reported by some,21 but not all,24 indicating that absence of TGF-β contributes to disease progression.21

In vivo studies investigating the effects of TGF-β on atherosclerosis are sparse. ApoE −/− mice that were treated with tamoxifen (an antiestrogen) exhibited increased levels of TGF-β, which was associated with a decrease in initial plaque area.25 In addition, TGF-β1 +/− mice that were treated with high cholesterol diet showed increased endothelial activation and lipid retention compared with TGF-β1 +/+ mice.26 The first in vivo correlation between plaque rupture and TGF-β was reported by Grainger et al,27 who showed that humans suffering from unstable angina have decreased plasma levels of TGF-β. However, the study by Mallat et al is the first in vivo intervention study that describes the effects of TGF-β in plaque progression and phenotype in primary atherosclerosis.

Mallat et al treated ApoE −/− mice for a long period (9 weeks) with a neutralizing antibody that inhibits TGF-β1, -β2, and -β3. As may be expected from such an approach, they did observe systemic effects.17 The authors correctly mention in the article that some of these systemic effects of anti–TGF-β treatment might have confounded their results. Indeed, besides the effects of TGF-β inhibition on inflammation and fibrosis in atherosclerotic lesions, treatment also induced inflammatory changes in the heart and resulted in a 3-fold increase in CD3-positive cells in the adventitia, suggesting a systemic vasculitis. Therefore, the question raises whether the systemic effects are due to local inhibition of TGF-β or a generalized immunosuppression. Mallat et al were able to find decreased levels of phospho-Smad2, indicating that the effects were mediated by TGF-β17; however, measurement of systemic inflammatory parameters in serum, such as CRP, TNFα, IL-6, etc, and whole body autopsy would have been more appropriate to exclude systemic inflammation.

As has been reported, vasculitis, as well as other systemic inflammatory diseases, are able to accelerate and aggravate atherosclerosis. Patients suffering from Takayasu arteritis have an increased incidence of advanced atherosclerotic lesions compared to their age matched controls.28 This is also true for patients suffering from systemic lupus erythematosus (SLE). In both the carotid and coronary arteries of patients with SLE, the extent of atherosclerosis is 30% to 50% more than in age matched controls. 29,30 In a large prospective population study (Bruneck Study31), it was shown that even common infections, such as respiratory infections, urinary tract infections, dental infections, or other infections, amplify the risk of atherosclerosis. Atherosclerotic risk was highest among subjects with chronic infections. Furthermore, the association between chlamydia pneumonia infection and atherosclerosis is also thought to result from systemic inflammation rather than from direct infection of the atherosclerotic plaque.32

Using a different approach, we found similar results as reported by Mallat et al.17 In a recent study, we treated ApoE −/− mice with a murine TGF-βRII fusion protein (TGF-βRII:Fc), which acts as a competitive inhibitor of TGF-β signaling (data will be presented at the Scientific Sessions of the AHA, November 2001). As Mallat et al have shown,17 we also observed a profound increase in inflammatory cells and mediators in initial and advanced atherosclerotic plaques after TGF-β inhibition, whereas the amount of fibrosis had decreased. Moreover, in advanced atherosclerotic plaques, the increase in inflammation and decrease in fibrosis in plaques were associated with a significant increase in the frequencies of recent and older intraplaque bleedings, fibrin deposition, iron deposition, and small plaque ruptures with disruption of the endothelial coverage after TGF-βRII:Fc treatment.

These data provide in vivo evidence that inhibition of TGF-β signaling induces characteristics of plaque instability in mouse atherosclerotic plaques. The data indicate that TGF-β plays an important role as immunomodulator and in extracellular matrix biology in atherosclerotic lesions. Thus, activation of TGF-β–signaling may provide a therapeutic target in atherosclerosis. It might not prevent the initiation of atherosclerosis, but it may prevent the transition into an unstable plaque phenotype due to its immunosuppressive and profibrotic effects.

Acknowledgments

E.L. is a postdoctoral fellow of the Dr E. Dekker program of the Dutch Heart Foundation (D2000-42).

Footnotes

  • The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

  1. ↵
    Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
    OpenUrlCrossRefPubMed
  2. ↵
    Class CK, Witztum JL. Atherosclerosis: the road ahead. Cell. 2001; 104: 503–516.
    OpenUrlCrossRefPubMed
  3. ↵
    Emeson EE, Robertson AL. T lymphocytes in aortic and coronary intimas: their potential role in atherogenesis. Am J Pathol. 1988; 130: 369–376.
    OpenUrlPubMed
  4. ↵
    Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000; 20: 1262–1275.
    OpenUrlFREE Full Text
  5. ↵
    Lutgens E, Gorelik L, Daemen MJAP, de Muinck ED, Grewal IS, Kotelianski VE, Flavell RA. Requirement for CD154 in the progression of atherosclerosis. Nat Med. 1999; 5: 1313–1316.
    OpenUrlCrossRefPubMed
  6. ↵
    Lutgens E, Cleutjens KBJM, Heeneman S, Koteliansky VE, Burkly LC, Daemen MJAP. Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype. Proc Natl Acad Sci U S A. 2000; 97: 7464–7469.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Lutgens E, Daemen MJAP. CD40-CD40L interactions in atherosclerosis. Trends Cardiovasc Med. 2001. In press.
  8. ↵
    Mach F, Schönbeck U, Sukhova GK, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature. 1998; 394: 200–203.
    OpenUrlCrossRefPubMed
  9. ↵
    Schönbeck U, Sukhova GK, Shimizu K, Mach F, Libby P. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc Natl Acad Sci U S A. 2000; 97: 7458–7463.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Qiao J, Tripathi J, Mishra NK, Cai Y, Tripathi S, Wang X, Imes S, Fishbein MC, Clinton SK, Libby P, Lusis AJ, Rajavashisth TB. Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am J Pathol. 1997; 150: 1687–1699.
    OpenUrlPubMed
  11. ↵
    Rajavashisth T, Qiao JH, Tripathi S, Tripathi J, Mishra N, Hua M, Wang XP, Loussararian A, Clinton S, Libby P, Lusis A. Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor–deficient mice. J Clin Invest. 101: 2702–2710.
  12. ↵
    Aiello RJ, Bourassa PAK, Lindsey S, Weng W, Natoli E, Rollins BJ, Milos P. Monocyte chemoattractant protein-1 accelerates atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 1999; 19: 1518–1525.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Gupta S, Pablo AM, Jiang XC, Wang N, Tall AR, Schindler C. IFN-γ potentiates atherosclerosis in ApoE knock-out mice. J Clin Invest. 1997; 99: 2752–2761.
    OpenUrlCrossRefPubMed
  14. ↵
    Pinderski Oslund LJ, Hedrick CC, Olvera T, Hagenbaugh A, Territo M, Berliner JA, Fyfe AI. Interleukin-10 blocks atherosclerotic events in vitro and in vivo. Arterioscler Thromb Vasc Biol. 1999; 19: 2847–2853.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Mallat Z, Besnard S, Duriez M, Deleuze V, Emmanuel F, Bureau MF, Soubrier F, Esposito B, Duez H, Fievet C, Staels B, Duverger N, Scherman D, Tedgui A. Protective role of interleukin-10 in atherosclerosis. Circ Res. 1999; 85: e17–e24.
  16. ↵
    Lamontagne D, Pohl U, Busse R. Mechanical deformation of vessel wall and shear stress determine the basal release of endothelium-derived relaxing factor in the intact rabbit coronary vascular bed. Circ Res. 1992; 70: 123–130.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    Mallat Z, Gojova A, Marchiol-Fournigault C, Esposito B, Kamaté C, Merval R, Fradelizi D, Tedgui A. Inhibition of transforming growth factor-β signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res. 2001; 89: 930–934.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Majesky MW, Lindner V, Twardizik DR, Schwartz SM, Reidy MA. Production of transforming growth factor-β1 during repair of arterial injury. J Clin Invest. 1991; 88: 904–910.
  19. ↵
    Schulick AH, Taylor AJ, Zuo W, Qiu C, Dong G, Woodward RN, Agah R, Roberts AB, Virmani R, Dichek DA. Overexpression of transforming growth factor-β1 in arterial endothelium causes hyperplasia, apoptosis and cartilaginous metaplasia. Proc Natl Acad Sci U S A. 1998; 95: 6983–6988.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    Smith JD, Bryant SR, Couper LL, Vary CPH, Gotwals PJ, Koteliansky VE, Lindner V. Soluble transforming growth factor-β type II receptor inhibits negative remodeling, fibroblast differentiation and intimal lesion formation, but not endothelial growth. Circ Res. 1999; 84: 1212–1222.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    McCaffrey TA. TGFβs and TGFβ receptors in atherosclerosis. Cytokine Growth Factor Rev. 2000; 11: 103–114.
    OpenUrlCrossRefPubMed
  22. ↵
    McCaffrey TA, Du B, Fu C, Bray PJ, Sanborn TA, Deutsch E, Tarazona N Shaknovitch A, Newman G, Patterson C, Bush HL. The expression of TGFβ receptors in human atherosclerosis: evidence for acquired resistance to apoptosis due to receptor imbalance. J Mol Cell Cardiol. 1999; 31: 1627–1642.
    OpenUrlCrossRefPubMed
  23. ↵
    Bobik A, Agrotis A, Kanellakis P, Dilley R, Krushinsky A, Smirnov V, Tararak E, Condron M, Kostolias G. Distinct patterns of Transforming growth factor-β isoform and receptor expression in human atherosclerotic lesions: colocalization implicates TGF-β in fibrofatty lesion development. Circulation. 1999; 99: 2883–2891.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Clark KJ, Cary NR, Grace AA, Metcalfe JC. Microsatellite mutation of type II transforming growth factor-β receptor is rare in atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2001; 21: 555–559.
    OpenUrlAbstract/FREE Full Text
  25. ↵
    Reckless J, Metcalfe JC, Grainger DJ. Tamoxifen decreases cholesterol sevenfold and abolishes lipid lesion development in apolipoprotein E knockout mice. Circulation. 1997; 95: 1542–1548.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    Grainger DJ, Mosedale DE, Metcalfe JC, Bottinger EP. Dietary fat and reduced levels of TGFβ1 act synergistically to promote activation of the vascular endothelium and formation of lipid lesions. J Cell Sci. 2000; 113: 2355–2361.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    Grainger DJ, Kemp PR, Metcalfe JC, Liu AC, Lawn RM, Williams NR, Grace AA, Schofield PM, Chauhan A. The serum concentration of active transforming growth factor-β is severely depressed in advanced atherosclerosis. Nat Med. 1995; 1: 74–79.
    OpenUrlCrossRefPubMed
  28. ↵
    Numano F, Kishi Y, Tanaka A, Ohkawara M, Kakuta T, Kobayashi Y. Inflammation and atherosclerosis: atherosclerotic lesions in Takayasu arteritis. Ann N Y Acad Sci. 2000; 902: 65–76.
    OpenUrlPubMed
  29. ↵
    Roman MJ, Salmon JE, Sobel R, Lockshin MD, Sammaritano L, Schwartz JE, Devereux RB. Prevalence and relation to risk factors of carotid artery atherosclerosis and left ventricular hypertrophy in systemic lupus erythematosus and antiphospholipid antibody syndrome. Am J Cardiol. 2001; 87: 663–666.
    OpenUrlCrossRefPubMed
  30. ↵
    Karrar A, Sequeira W, Block JA. Coronary artery disease in systemic lupus erythematosus: a review of the literature. Semin Arthritis Rheum. 2001; 30: 436–443.
    OpenUrlCrossRefPubMed
  31. ↵
    Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhollenzer F, Muggeo M, Xu Q, Wick G, Poewe W, Willeit J. Chronic infections and the risk of carotid atherosclerosis: prospective results from a large population study. Circulation. 2001; 103: 1064–1070.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    Virok D, Kis Z, Karai L, Intzedy L, Burian K, Szabo A, Ivanyi B, Gonczol E. Chlamydia pneumoniae in atherosclerotic middle cerebral artery. Stroke. 2001; 32: 1973–1978.
    OpenUrlAbstract/FREE Full Text
View Abstract
Back to top
Previous ArticleNext Article

This Issue

Circulation Research
November 9, 2001, Volume 89, Issue 10
  • Table of Contents
Previous ArticleNext Article

Jump to

  • Article
    • Acknowledgments
    • Footnotes
    • References
  • Info & Metrics

Article Tools

  • Print
  • Citation Tools
    Transforming Growth Factor-β
    Esther Lutgens and Mat J.A.P. Daemen
    Circulation Research. 2001;89:853-855, originally published November 9, 2001

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
  • Article Alerts
    Log in to Email Alerts with your email address.
  • Save to my folders

Share this Article

  • Email

    Thank you for your interest in spreading the word on Circulation Research.

    NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

    Enter multiple addresses on separate lines or separate them with commas.
    Transforming Growth Factor-β
    (Your Name) has sent you a message from Circulation Research
    (Your Name) thought you would like to see the Circulation Research web site.
  • Share on Social Media
    Transforming Growth Factor-β
    Esther Lutgens and Mat J.A.P. Daemen
    Circulation Research. 2001;89:853-855, originally published November 9, 2001
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Related Articles

Cited By...

Circulation Research

  • About Circulation Research
  • Editorial Board
  • Instructions for Authors
  • Abstract Supplements
  • AHA Statements and Guidelines
  • Permissions
  • Reprints
  • Email Alerts
  • Open Access Information
  • AHA Journals RSS
  • AHA Newsroom

Editorial Office Address:
3355 Keswick Rd
Main Bldg 103
Baltimore, MD 21211
CircRes@circresearch.org

Information for:
  • Advertisers
  • Subscribers
  • Subscriber Help
  • Institutions / Librarians
  • Institutional Subscriptions FAQ
  • International Users
American Heart Association Learn and Live
National Center
7272 Greenville Ave.
Dallas, TX 75231

Customer Service

  • 1-800-AHA-USA-1
  • 1-800-242-8721
  • Local Info
  • Contact Us

About Us

Our mission is to build healthier lives, free of cardiovascular diseases and stroke. That single purpose drives all we do. The need for our work is beyond question. Find Out More about the American Heart Association

  • Careers
  • SHOP
  • Latest Heart and Stroke News
  • AHA/ASA Media Newsroom

Our Sites

  • American Heart Association
  • American Stroke Association
  • For Professionals
  • More Sites

Take Action

  • Advocate
  • Donate
  • Planned Giving
  • Volunteer

Online Communities

  • AFib Support
  • Garden Community
  • Patient Support Network
  • Professional Online Network

Follow Us:

  • Follow Circulation on Twitter
  • Visit Circulation on Facebook
  • Follow Circulation on Google Plus
  • Follow Circulation on Instagram
  • Follow Circulation on Pinterest
  • Follow Circulation on YouTube
  • Rss Feeds
  • Privacy Policy
  • Copyright
  • Ethics Policy
  • Conflict of Interest Policy
  • Linking Policy
  • Diversity
  • Careers

©2018 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. The American Heart Association is a qualified 501(c)(3) tax-exempt organization.
*Red Dress™ DHHS, Go Red™ AHA; National Wear Red Day ® is a registered trademark.

  • PUTTING PATIENTS FIRST National Health Council Standards of Excellence Certification Program
  • BBB Accredited Charity
  • Comodo Secured